Hybrid polypeptides with enhanced pharmacokinetic properties

ABSTRACT

The present invention relates to enhancer peptide sequences originally derived from various retroviral envelope (gp41) protein sequences that enhance the pharmacokinetic properties of any core polypeptide to which they are linked. The invention is based on the discovery that hybrid polypeptides comprising the enhancer peptide sequences linked to a core polypeptide possess enhanced pharmacokinetic properties such as increased half life. The invention further relates to methods for enhancing the pharmacokinetic properties of any core polypeptide through linkage of the enhancer peptide sequences to the core polypeptide. The core polypeptides to be used in the practice of the invention can include any pharmacologically useful peptide that can be used, for example, as a therapeutic or prophylactic reagent.

This is a continuation of application Ser. No. 09/082,279 filed May 20, 1998, now U.S. Pat. No. 6,258,782 issued Jul. 10, 2001, the contents of which are incorporated herein by reference.

1. INTRODUCTION

The present invention relates to enhancer peptide sequences originally derived from various retroviral envelope (gp4l) protein sequences that enhance the pharmacokinetic properties of any core polypeptide to which they are linked. The invention is based on the discovery that hybrid polypeptides comprising the enhancer peptide sequences linked to a core polypepide possess enhanced pharmacokinetic properties such as increased half life. The invention further relates to methods for enhancing the pharmacokinetic properties of any core polypeptide through linkage of the enhancer peptide sequences to the core polypeptide. The core polypeptides to be used in the practice of the invention can include any pharmacologically useful peptide that can be used, for example, as a therapeutic or prophylactic reagent. In a non-limiting embodiment, the invention is demonstrated by way of example wherein a hybrid polypeptide comprising, for example, an HIV core polypeptide linked to enhancer peptide sequences, is shown to be a potent, non-cytotoxic inhibitor of HIV-1, HIV-2 and SIV infection. Additionally, the enhancer peptide sequences of the invention have been linked to a respiratory syncytial virus (RSV) core polypeptide and a luteinizing hormone receptor (LH-RH) core polypeptide. In each instance, the hybrid polypeptide was found to possess enhanced pharmacokinetic properties, and the RSV hybrid polypeptide exhibited substantial anti-RSV activity.

The Sequence Listing for this application is on duplicate compact discs labeled “Copy 1” and “Copy 2”. Copy 1 and Copy 2 each contain only one file named “7872081.APP” which was created on Aug. 10, 2001 and is 645,776 bytes. The entire contents of each of the compact discs is incorporated herein by reference.

2. BACKGROUND OF THE INVENTION

Polypeptide products have a wide range of uses as therapeutic and/or prophylactic reagents for prevention and treatment of disease. Many polypeptides are able to regulate biochemical or physiological processes to either prevent disease or provide relief from symptoms associated with disease. For example, polypeptides such as viral or bacterial polypeptides have been utilized successfully as vaccines for prevention of pathological diseases. Additionally, peptides have been successfully utilized as therapeutic agents for treatment of disease symptoms. Such peptides fall into diverse categories such, for example, as hormones, enzymes, immunomodulators, serum proteins and cytokines.

For polypeptides to manifest their proper biological and therapeutic effect on the target sites, the polypeptides must be present in appropriate concentrations at the sites of action. In addition, their structural integrity must generally be maintained. Therefore, the formulation of polypeptides as drugs for therapeutic use is directed by the chemical nature and the characteristics of the polypeptides, such as their size and complexity, their conformational requirements and their often complicated stability, and solubility profiles. The pharmacokinetics of any particular therapeutic peptide is dependent on the bioavailability, distribution and clearance of said peptide.

Since many bioactive substances, such as peptides and proteins, are rapidly destroyed by the body, it is critical to develop effective systems for maintaining a steady concentration of peptide in blood circulation, to increase the efficacy of such peptides, and to minimize the incidence and severity of adverse side effects.

3. SUMMARY OF THE INVENTION

The present invention relates, first, to enhancer peptide sequences derived from various retroviral envelope (gp41) protein sequences i.e., HIV-1, HIV-2 and SIV, that enhance the pharmacokinetic properties of any core. polypeptide to which they are linked. The invention is based on the surprising result that when the disclosed enhancer peptide sequences are linked to any core polypeptide, the resulting hybrid polypeptide possesses enhanced pharmacokinetic properties including, for example, increased half life and reduced clearance rate relative to the core polypeptide alone. The present invention further relates to such hybrid polypeptides and core polypeptides.

The core polypeptides to be used in the practice of the invention can comprise any peptides which may be introduced into a living system, for example, any peptides capable of functioning as therapeutic or prophylactic reagents useful for treatment or prevention of disease. Such peptides include, for example, growth factors, hormones, cytokines, angiogenic growth factors, extracellular matrix polypeptides or polypeptides that exhibit antifusogenic and/or antiviral activity, and peptides or polypeptides that function as immunogens including, for example, viral and bacterial polypeptides.

The invention further relates to methods for enhancing the pharmacokinetic properties of any core polypeptide through linkage of the core polypeptide to the enhancer peptide sequences to form hybrid polypeptides.

The invention is demonstrated by way of examples wherein hybrid polypeptides containing an HIV core polypeptide linked to enhancer peptide sequences are shown to exhibit greatly enhanced pharmacokinetic properties and act as a potent, non-cytotoxic inhibitors of HIV-1, HIV-2 and SIV infection. The invention is further demonstrated by examples wherein hybrid polypeptides; containing an RSV core polypeptide or a luteinizing hormone polypeptide are shown to exhibit greatly enhanced pharmacokinetic properties. In addition, the RSV hybrid polypeptide exhibited substantial anti-RSV activity.

3.1. DEFINITIONS

Peptides are defined herein as organic compounds comprising two or more aminoacids covalently joined by peptide bonds. Peptides may be referred to with respect to the number of constituent natural L-amino acids, i.e., a dipeptide contains two amino acid residues, a tripeptide contains three, etc. Peptides containing ten or fewer amino acids may be referred to as oligopeptides, while those with more than ten amino acid residues are polypeptides. Such peptides may also include non-natural amino acids and any of the modifications and additional amino and carboxyl groups as are described herein.

Peptide sequences defined herein are represented by one-letter symbols for amino acid residues as follows:

A (alanine)

R (arginine),

N (asparagine)

D (aspartic acid)

C (cysteine)

Q (glutamine)

E (glutamic acid)

G (glycine)

H (histidine)

I (isoleucine)

L (leucine)

K (lysine)

M (methionine)

F (phenylalanine)

P (proline)

S (serine)

T (threonine)

W (tryptophan)

Y (tyrosine)

V (valine)

X (any amino acid)

“Enhancer peptide sequences” are defined as peptides having the following consensus amino acid sequences: “WXXWXXXI”, “WXXWXXX”, “WXXWXX”, “WXXWX”, “WXXW”, “WXXXWXWX”, “XXXWXWX”, “XXWXWX”, “XWXWX”, “WXWX”, “WXXXWXW”, “WXXXWX”, “WXXXW”, “IXXXWXXW”, “XXXWXXW”, “XXWXXW”, “XWXXW ”, “XWXWXXXW”, “XWXWXXX”, “XWXWXX”, “XWXWX”, “XWXW”, “WXWXXXW”, or “XWXXXW”, wherein X can be any amino acid, W represents tryptophan and I represents isoleucine. As discussed below, the enhancer peptide sequences of the invention also include peptide sequences that are otherwise the same as the consensus amino acid sequences but contain amino acid substitutions, insertions or deletions but which do not abolish the ability of the peptide to enhance the pharmacokinetic properties of a core peptide to which it is linked.

“Core polypeptide” as used herein, refers to any polypeptide which may be introduced into a living system and, thus, represents a bioactive molecule, for example any polypeptide that can function as a pharmacologically useful peptide for treatment or prevention of disease.

“Hybrid polypeptide” as used herein, refers to any polypeptide comprising a terminal enhancer peptide sequence and a core polypeptide.

4. BRIEF DESCRIPTION OF DRAWINGS

FIG. 1. Hybrid polypeptides. Enhancer peptide sequences derived from putative N-terminal and C-terminal interactive regions are depicted linked to a core polypeptide. The critical enhancer peptide sequences are shaded. It is to be noted that the enhancer peptide sequences indicated may be used either as N- or C- terminal additions. Further, the enhancer peptide sequences can be added to a core polypeptide in forward or reverse orientation, individually or in any of the possible combinations, to enhance pharmacokinetic properties of the peptide.

FIG. 2A. Enhancer peptide sequences derived from various envelope (gp41) protein sequences, representing the N-terminal interactive region observed in all currently published isolate sequences of HIV-1, HIV-2 and SIV. The final sequence “WXXWXXXI” (SEQ ID NO: 1475) represents a consensus sequence.

FIG. 2B. Enhancer peptide sequence variants derived from various envelope (gp4 1) protein sequences, representing the C-terminal interactive region observed in all currently published isolate sequences of HIV-1, HIV-2 and SIV. The final sequence “WXXXWXWX” (SEQ ID NO: 1515) represents a consensus sequence.

FIG. 3. Comparison of HIV-1 titres in tissues of HIV-1 9320 infected SCID-HuPBMC mice as measured by P24 Levels in HuPBMC co-culture assays. The figure shows a comparison of in vivo T20 and T1249 viral inhibition.

FIGS. 4A-4B. Plasma pharmacokinetic profile of T1249 vs T1387 core control in CD-rats following IV injection for up to 2 hrs (FIG. 4A) and 8 hrs (FIG. 4B). The T1387 polypeptide is a core polypeptide and the T1249 polypeptide is the core polypeptide linked to enhancer peptide sequences.

FIG. 5. Plasma pharmacokinetic profile of T1249 vs T20 control in CD-rats following IV administration. The T1249 polypeptide is a hybrid polypeptide of a core polypeptide (T1387) linked to enhancer peptide sequences. T20: n=4; T1249: n=3.

FIG. 6. Comparison of T20/T1249 Anti-HIV-1/IIIb activity and cytotoxicity.

FIGS. 7A-7B-1. Direct Binding of T1249 to gp41 construct M41Δ178. ¹²⁵I-T1249 was HPLC purified to maximum specific activity. Saturation binding to M41Δ178 (a gp41 ectodomain fusion protein lacking the T20 amino acid sequence) immobilized in microtitre plates at 0.5 mg/ml is shown.

FIGS. 8A-8B. Time Course of T1249 Association/ Dissociation. Dissociation of bound radioligand was measured following the addition of unlabeled peptide to a final concentration of 10 μM in {fraction (1/10)} total assay volume.

FIGS. 9A-B. Competition for T1249 Binding to M41Δ178. Unlabeled T1249 and T20 were titrated in the presence of a single concentration of either ¹²⁵I-T1249 or ¹²⁵I-T20. Ligand was added just after the unlabeled peptide to start the incubation.

FIGS. 10A-10B. Plasma pharmacokinetic profile of RSV hybrid polypeptides T1301 (10A) and T1302 (10B) vs T786 in CD rats.

FIG. 11A. Plaque Reduction Assay. Hybrid polypeptide T1293 is capable of inhibiting RSV infection with an IC₅₀ 2.6 μg/ml.

FIG. 11B. Plaque Reduction Assay demonstrates the ability of RSV Hybrid Polypeptides T1301, T1302 and T1303 to inhibit RSV infection.

FIGS. 12A and 12B. Plasma pharmacokinetic profile of luteinizing hormone hybrid polypeptide T1324 vs T1323 in CD male rats. The T1323 polypeptide is a luteinizing hormone core polypeptide and the T1324 polypeptide is a hybrid polypeptide comprising a core polypeptide linked to enhancer peptide sequences.

FIGS. 13A-13D. Hybrid polypeptide sequences derived from various core polypeptides. Core polypeptide sequences are shown shaded.

5. DETAILED DESCRIPTION OF THE INVENTION

Described herein are peptide sequences, referred to as enhancer peptide sequences, derived from various retroviral envelope (gp41) protein sequences that are capable of enhancing the pharmacokinetic properties of core polypeptides to which they are linked. Such enhancer peptide sequences can be utilized in methods for enhancing the pharmacokinetic properties of any core polypeptide through linkage of the enhancer peptide sequences to the core polypeptide to form a hybrid polypeptide with enhanced pharmacokinetic properties relative to the core polypeptide alone.

The core polypeptides of the hybrid polypeptides of the invention comprise any peptide which may be introduced into a living system, for example, any peptide that can function as a therapeutic or prophylactic reagent useful for treatment or prevention of disease.

5.1. HYBRID POLYPEPTIDES

The hybrid polypeptides of the invention comprise at least one enhancer peptide sequence and a core polypeptide. The enhancer peptide sequences of the invention comprise peptide sequences originally derived from various retroviral envelope (gp 41) protein sequences including HIV-1, HIV-2 and SIV. While not wishing to be bound by any particular theory, the structure of the envelope protein is such that the putative α-helix region located in the C-terminal region of the protein is believed to associate with the leucine zipper region located in the N-terminal region of the protein. Alignment of the N-terminal and C-terminal enhancer peptide sequence gp4l regions observed in all currently published isolate sequences of HIV-1, HIV-2 and SIV identified consensus amino acid sequences.

In particular the following consensus amino acid sequences were identified (the consensus sequences are listed below in forward and reverse orientations because said enhancer sequences can be utilized either in forward or reverse orientation): “WXXWXXXI”, “WXXWXXX”, “WXXWXX”, “WXXWX”, “WXXW”, “WXXXWXWX”, “XXXWXWX”, “XXWXWX”, “XWXWX”, “WXWX”, “WXXXWXW”, “WXXXWX”, “WXXXW”, “IXXXWXXW”, “XXXWXXW”, “XXWXXW”, “XWXXW”, “XWXWXXXW”, “XWXWXXX”, “XWXWXX”, “XWXWX”, “XWXW”, “WXWXXXW”, or “XWXXXW”, wherein X can be any amino acid, W represents tryptophan and I represents isoleucine. Forward orientations of consensus amino acid sequences are shown in FIGS. 1 and 2.

In a preferred embodiment of the invention, enhancer peptide sequences which may be used to enhance the pharmacokinetic properties of the resultant hybrid polypeptides comprise the enhancer sequences depicted in FIG. 2. In another preferred embodiment, enhancer peptide sequences of the invention comprise the enhancer peptide sequences depicted in FIG. 2 exhibiting conserved amino acid substitutions at one or more residues wherein said substitutions do not abolish the ability of the enhancer peptide sequence to enhance the pharmacokinetic properties of a hybrid polypeptide relative to its corresponding core polypeptide. Among the most preferred enhancer peptide sequences are ones comprising the following amino sequence: “WQEWEQKI”(SEQ ID NO: 1129) and “WASLWEWF”(SEQ ID NO:1144 residue #19-26).

The present invention further provides enhancer peptide sequences comprising amino acid sequences of FIGS. 1 and 2 that are otherwise the same, but, that said enhancer peptide sequences comprise one or more amino acid substitutions, additions (generally no greater than about 15 amino acid residues in length) or deletions (for example, amino- or terminal- truncations) which nevertheless are able to increase the pharmacokinetic properties of core polypeptides to which they are linked relative to core polypeptides without such enhancer sequences.

In particular, it is understood that certain amino acid residues comprising the consensus amino acid sequence of the enhancer peptide sequences can be replaced with other amino acid residues without significantly deleteriously affecting, and in some instances even enhancing, the activity of the peptides. Thus, also contemplated by the present invention are altered forms of the enhancer peptide sequence wherein at least one defined amino acid residue in the structure is substituted with another amino acid residue. Such amino acid substitutions may be conservative i.e., the replacing amino acid residue has physical and chemical properties (e.g., similar charge, size and/or hydrophobicity characteristics) that are similar to the amino acid residue being replaced, or non-conservative amino acid substitutions.

A critical feature affecting the activity of the peptides of the invention is their ability to increase the pharmacokinetic properties of core polypeptides to which they are linked relative to the core polypeptides above, thus it will be recognized that in preferred embodiments of the invention, the amino acid substitutions do not affect the ability of the enhancer peptides to increase the pharmacokinetic properties of the peptide. In general, such changes involve the “X” amino acid residues of the enhancer peptide consensus sequences.

In addition, the amino acid substitutions need not be, and in certain embodiments preferably are not, restricted to the genetically encoded amino acids. Indeed, the peptides may contain genetically non-encoded amino acids. Thus, in addition to the naturally occurring genetically encoded amino acids, amino acid residues in the peptides may be substituted with naturally occurring non-encoded amino acids and synthetic amino acids.

Certain commonly encountered amino acids which provide useful substitutions include, but are not limited to, β-alanine (β-Ala) and other omega-amino acids such as 3-aminopropionic acid, 2,3-diaminopropionic acid (Dpr), 4-aminobutyric acid and so forth; α-aminoisobutyric acid (Aib); ε-aminohexanoic acid (Aha); δ-aminovaleric acid (Ava); N-methylglycine or sarcosine (MeGly); ornithine (Orn); citrulline (Cit); t-butylalanine (t-BuA); t-butylglycine (t-BuG); N-methylisoleucine (MeIle); phenylglycine (Phg); cyclohexylalanine (Cha); norleucine (Nle); naphthylalanine (Nal); 4-chlorophenylalanine (Phe(4-Cl)); 2-fluorophenylalanine (Phe(2-F)); 3-fluorophenylalanine (Phe(3-F)); 4-fluorophenylalanine (Phe(4-F)); penicillamine (Pen); 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic); β-2-thienylalanine (Thi); methionine sulfoxide (MSO); homoarginine (hArg); N-acetyl lysine (AcLys); 2,4-diaminobutyric acid (Dbu); 2,3-diaminobutyric acid (Dab); p-aminophenylalanine (Phe(pNH₂)); N-methyl valine (MeVal); homocysteine (hCys), homophenylalanine (hphe) and homoserine (hSer); hydroxyprdline (Hyp), homoproline (hPro), N-methylated amino acids and peptoids (N-substituted glycines).

While in most instances, the amino acids of the peptide will be substituted with L-enantiomeric amino acids, the substitutions are not limited to L-enantiomeric amino acids. Thus, also included in the definition of “mutated” or “altered” forms are those situations where an L-amino acid is replaced with an identical D-amino acid (e.g., L-Arg→D-Arg) or with a D-amino acid of the same category or subcategory (e.g., L-Arg→D-Lys), and vice versa.

It is to be understood that the present invention also contemplates peptide analogues wherein one or more amide linkage is optionally replaced with a linkage other than amide, preferably substituted amide or an isostere of amide. Thus, while the amino acid residues within peptides are generally described in terms of amino acids, and preferred embodiments of the invention are exemplified by way of peptides, one having skill in the art will recognize that in embodiments having non-amide linkages, the term “amino acid” or “residue” as used herein refers to other bifunctional moieties bearing groups similar in structure to the side chains of the amino acids. In addition the amino acid residues may be blocked or unblocked.

Additionally, one or more amide linkages can be replaced with peptidomimetic or amide mimetic moieties which do not significantly interfere with the structure or activity of the peptides. Suitable amide mimetic moieties are described, for example, in Olson et al., 1993, J. Med. Chem. 36:3049.

Enhancer peptide sequences can be used to enhance the pharmacokinetic properties of the core polypeptide as either N-terminal or C-terminal additions. While it is preferable for the enhancer peptide sequences to be utilized in a pairwise fashion, that is, preferably hybrid polypeptides comprise an enhancer peptide sequence at both the amino- and carboxy-termini, hybrid polypeptides can also comprise a single enhancer peptide, said peptide present at either the amino- or carboxy- terminus of the hybrid polypeptide. Further, the enhancer peptides can be used in either forward or reverse orientation, or in any possible combination, linked to a core polypeptide. It is noted that any of the enhancer peptides can be introduced at either the N-terminus on the C-terminus of the core polypeptide.

It is understood that the core polypeptide may be linked to the enhancer peptides via a peptide amide linkage, although linkages other than amide linkages can be utilized to join the enhancer peptide sequences to the core polypeptides. Such linkages include for example any carbon—carbon, ester or chemical bond that functions to link the enhancer peptide sequences of the invention to a core peptide.

The amino- and/or carboxy-termini of the resulting hybrid polypeptide can comprise an amino group (—NH₂) or a carboxy (—COOH) group, respectively. Alternatively, the hybrid polypeptide amino-terminus may, for example, represent a hydrophobic group, including but not limited to carbobenzyl, dansyl, T-butoxycarbonyl, decanoyl, napthoyl or other carbohydrate group; an acetyl group; 9-fluorenylmethoxy-carbonyl (FMOC) group; or a modified, non-naturally occurring amino acid residue. Alternatively, the hybrid polypeptide carboxy-terminus can, for example, represent an amido group; a T-buxoxycarbonyl group; or a modified non-naturally occurring amino acid residue. As a non-limiting example, the amino- and/or carboxy-termini of the resulting hybrid polypeptide can comprise any of the amino- and/or carboxy-terminal modifications depicted in the peptides shown in FIGS. 13A-D or Table 1, below.

The core polypeptides to be used in the practice of the invention comprise any polypeptide which may be introduced into a living system, for example, any polypeptide that can function as a pharmacologically useful polypeptide. Such core polypeptides may be useful for the treatment or prevention of disease. Examples of possible core polypeptides include growth factors, cytokines, therapeutic polypeptides, hormones and peptide fragments of hormones, inhibitors of cytokines, peptide growth and differentiation factors, interleukins, chemokines, interferons, colony stimulating factors, angiogenic factors and extracellular matrix proteins such as collagen, laminin and fibronectin to name a few. In addition, possible core polypeptides may include viral or bacterial polypeptides that may function either directly or as immunogens, and thus may be useful in the treatment or prevention of pathological disease.

Representative examples of hybrid polypeptides which comprise core polypeptides derived from viral protein sequences are shown in FIGS. 13A-D. Core polypeptide sequences are shaded. Core polypeptides also include, but are not limited to, the polypeptides disclosed in U.S. Pat. No. 5,464,933, U.S. Pat. No. 5,656,480 and WO 96/19495, each of which is incorporated herein by reference in its entirety.

Core polypeptide sequences can further include, but are not limited to the core polypeptide sequences depicted in FIGS. 13A-D and Table 1, below.

TABLE 1 T Seq. No. Sequence ID No. 1 GIKQLQARILAVERYLKDQ 1 2 NNLLRAIEAQQHLLQLTVW 2 3 NEQELLELDKWASLWNWF 3 4 YTSLIHSLIEESQNQQEK 4 5 Ac-VWGIKQLQARILAVERYLKDQQLLGIWG-NH2 5 6 QHLLQLTVWGIKQLQARILAVERYLKDQ 6 7 LRAIEAQQHLLQLTVWGIKQLQARILAV 7 8 VQQQNNLLARIEAQQHLLQLTVWGIKQL 8 9 RQLLSGIVQQQNNLLRAIEAQQHLLQLT 9 10 MTLTVQARQLLSGIVQQQNNLLRAIEAQ 10 12 VVSLSNGVSVLTSKVLDLKNYIDKQLL 11 13 LLSTNKAVVSLSNGVSVLTSKVLDLKNY 12 15 Ac-VLHLEGEVNKIKSALLSTNKAVVSLSNG-NH2 13 19 Ac-LLSTNKAVVSLSNGVSVLTSKVLDLKNY-NH2 14 20 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 15 21 Ac-NNLLRAIEAQQHLLQLTVWGIKQLQARILAVERYLKDQ-NH2 16 22 Ac-IELSNIKENKCNGTDAKVKLIKQELDKYKNAVTELQLLMQST-NH2 17 23 Ac-IELSNIKENKCNGTDAKVKLIKQELDKY-NH2 18 24 Ac-ENKCNGTDAKVKLIKQELDKYKNAVTEL-NH2 19 25 Ac-DAKVKLIKQELDKYKNAVTELQLLMQST-NH2 20 26 Ac-CNGTDAKVKLIKQELDKYKNAVTELQLL-NH2 21 27 Ac-SNIKENKCNGTDAKVKLIKQELDKYKNAVTELQLL-NH2 22 28 Ac-ASGVAVSKVLHLEGEVNKIKSALLSTNKAVVSLSNGV-NH2 23 29 Ac-SGVAVSKVLHLEGEVNKIKSALLSTNKAVVSLSNG-NH2 24 30 Ac-VLHLEGEVNKIKSALLSTHKAVVSLSNGVSVLTSK-NH2 25 31 Ac-ARKLQRMKQLEDKVEELLSKNYHYLENEVARLKKLV-NH2 26 32 Ac-RMKQLEDKVEELLSKNYHYLENEVARLKKLVGER-NH2 27 33 Ac-VQQQNNLLRAIEAQQHLLQLTVWGIKQL-NH2 28 34 Ac-LRAIEAQQHLLQLTVWGIKQLQARILAV-NH2 29 35 Ac-QHLLQLTVWGIKQLQARILAVERYLKDQ-NH2 30 36 Ac-RQLLSGIVQQQNNLLRAIEAQQHLLQLT-NH2 31 37 Ac-MTLTVQARQLLSGIVQQQNNLLRAIEAQ-NH2 32 38 Ac-AKQARSDIEKLKEAIRDTNKAVQSVQSS-NH2 33 39 Ac-AAVALVEAKQARSDIEKLKEAIRDTNKAVQSVQSS-NH2 34 40 Ac-AKQARSDIEKLKEAIRDTNKAVQSVQSSIGNLIVA-NH2 35 41 Ac-GTIALGVATSAQITAAVALVEAKQARSD-NH2 36 42 Ac-ATSAQITAAVALVEAKQARSDIEKLKEA-NH2 37 43 Ac-AAVALVEAKQARSDIEKLKEAIRDTNKA-NH2 38 44 Ac-IEKLKEAIRDTNKAVQSVQSSIGNLIVA-NH2 40 45 Ac-IRDTNKAVQSVQSSIGNLIVAIKSVQDY-NH2 41 46 Ac-AVQSVQSSIGNLIVAIKSVQDYVNKEIV-NH2 42 47 Ac-QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLARILAVERYLKDQ-NH2 43 48 Ac-QARQLLSGIVQQQNNLLRAIEAQQHLLQ-NH2 43 49 Ac-MTWMEMDREINNYTSLIGSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 45 50 Ac-WMEWDRENNYTSLIGSLIEESQNQQEKNEQELLE-NH2 46 51 Ac-INNYTSLIGSLIEESQNQQEKNEQELLE-NH2 47 52 Ac-INNYTSLIGSLIEESQNQQEKNEQELLELDKWASL-NH2 48 53 Ac-EWDREINNYTSLIGSLIEESQNQQEKNEQEGGC-NH2 49 54 Ac-QSRTLLAGIVQQQQQLLDVVKRQQELLR-NH2 50 55 Ac-NNDTWQEWERKVDFLEENITALLEEAQIQQEKNMYELQKLNSWD-NH2 51 56 Ac-WQEWERKVDFLEENITALLEEAQIQQEK-NH2 52 57 Ac-VDFLEENITALLEEAQIQQEKNMYELQK-NH2 53 58 Ac-ITALLEEAQIQQEKNMYELQKLNSWDVF-NH2 54 59 Ac-SSESFTLLEQWNNWKLQLAEQWLEQINEKHYLEDIS-NH2 55 60 Ac-DKWASLWNWF-NH2 56 61 Ac-NEQELLELDKWASLWNWF-NH2 57 62 Ac-EKNEQELLELDKWASLWNWF-NH2 58 63 Ac-NQQEKNEQELLELDKWASLWNWF-NH2 59 64 Ac-ESQNQQEKNEQELLELDKWASLWNWF-NH2 60 65 Ac-LIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 61 66 Ac-NDQKKLMSNNVQIVRQQSYSIMSIIKEE-NH2 62 67 Ac-DEFDASISQVNEKINQSLAFIRKSDELL-NH2 63 68 Ac-VSKGYSALRTGWYTSVITIELSNIKEN-NH2 64 69 Ac-VVSLSNGVSVLTSKVLDLKNYIDKQLL-NH2 65 70 Ac-VNKIKSALLSTNKAVVSLSNGVSVLTSK-NH2 66 71 Ac-PIINFYDPLVFPSDEFDASISQVNEKINQSLAFIR-NH2 67 72 Ac-NLVYAQLQFTYDTLRGYINRALAQIAEA-NH2 68 73 Ac-LNQVDLTETLERYQQRLNTYALVSKDASYRS-NH2 69 74 Ac-ELLVLKKAQLNRHSYLKDSDFLDAALD-NH2 70 75 Ac-LAEAGEESVTEDTEREDTEEEREDEEE-NH2 71 76 Ac-ALLAEAGEESVTEDTEREDTEEEREDEEEENEART-NH2 72 77 Ac-ETERSVDLVAALLAEAGEESVTEDTEREDTEEERE-NH2 73 78 Ac-EESVTEDTEREDTEEEREDEEEENEART-NH2 74 79 Ac-VDLVAALLAEAGEESVTEDTEREDTEEE-NH2 75 80 Ac-NSETERSVDLVAALLAEAGEESVTE-NH2 76 81 Ac-DISYAQLQFTYDVLKDYINDALRNIMDA-NH2 77 82 Ac-SNVFSKDEIMREYNSQKQHIRTLSAKVNDN-NH2 78 83 Biotin-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 1076 84 Dig-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 1076 85 Biotin-NNLLRAIEAQQHLLQLTVWGIKQLQARILAVERYLKDQ-NH2 16 86 Dig-NNLLRAIEAQQHLLQLTVWGIKQLQARILAVERYLKDQ-NH2 16 87 Ac-VLHQLNIQLKQYLETQERLLAGNRIAARQLLQIWKDVA-NH2 83 88 Ac-LWHEQLLNTAQRAGLQLQLINQALAVREKVLIRYDIQK-NH2 84 89 Ac-LLDNFESTWEQSKELWEQQEISIQNLHKSALQEYW-NH2 85 90 Ac-LSNLLQISNNSDEWLEALEIEHEKWKLTQWQSYEQF-NH2 86 91 Ac-KLEALEGKLEALEGKLEALEGKLEALEGKLEALEGK-NH2 87 92 Ac-ELRALRGELRALRGELRALRGELRALRGK-NH2 88 93 Ac-ELKAKELEGEGLAEGEEALKGLLEKAAKLEGLELLK-NH2 89 94 Ac-WEAAAREAAAREAAAREAAARA-NH2 90 95 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNAF-NH2 91 96 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASLANWF-NH2 92 97 Ac-YTSLIHSLIEESQNQQEKNQQELLELDKWASLWNWF-NH2 93 98 Ac-YTSLIHSLIEESQNQQEKNEQELLQLDKWASLWNWF-NH2 94 99 Ac-YTSLIHSLIEESQNQQEKNQQELLQLDKWASLWNWF-NH2 95 100 Ac-RMKQLEDKVEELLSKNYHLENEVARLKKLVGER-NH2 96 101 Ac-QQLLQLTVWGIKQLQARILAVERYLKNQ-NH2 97 102 Ac-NEQELLELDKWASLWNWF-NH2 98 103 Ac-YTSLIQSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 99 104 Ac-IINFYDPLVFPSDEFDASISQVNEKINQSLAFIRK-NH2 100 105 Ac-INFYDPLVFPSDEFDASISQVNEKINQSLAFIRKS-NH2 101 106 Ac-NFYDPLVFPSDEFDASISQVNEKINQSLAFIRKSD-NH2 102 107 Ac-FYDPLVFPSDEFDASISQVNEKINQSLAFIRKSDE-NH2 103 108 Ac-YDPLVFPSDEFDASISQVNEKINQSLAFIRKSDEL-NH2 104 109 Ac-DPLVFPSDEFDASISQVNEKINQSLAFIRKSDELL-NH2 105 110 Ac-PLVFPSDEFDASISQVNEKINQSLAFIRKSDELLH-NH2 106 111 Ac-LVFPSDEFDASISQVNEKINQSLAFIRKSDELLHN-NH2 107 112 Ac-VFPSDEFDASISQVNEKINQSLAFIRKSDELLHNV-NH2 108 113 Ac-FPSDEFDASISQVNEKINQSLAFIRKSDELLHNVN-NH2 109 114 Ac-PSDEFDASISQVNEKINQSLAFIRKSDELLHNVNA-NH2 110 115 Ac-SDEFDASISQVNEKINQSLAFIRKSDELLHNVNAG-NH2 111 116 Ac-DEFDASISQVNEKINQSLAFIRKSDELLHNVNAGK-NH2 112 117 Ac-EFDASISQVNEKINQSLAFIRKSDELLHNVNAGKS-NH2 113 118 Ac-FDASISQVNEKINQSLAFIRKSDELLHNVNAGKST-NH2 114 119 Ac-DASISQVNEKINQSLAFIRKSDELLHNVNAGKSTT-NH2 115 120 Ac-ASGVAVSKVLHLEGEVNKIKSALLSTNKAVVSLSN-NH2 116 121 Ac-SGVAVSKVLHLEGEVNKIKSALLSTNKAVVSLSNG-NH2 117 122 Ac-GVAVSKVLHLEGEVNKIKSALLSTNKAVVSLSNGV-NH2 118 123 Ac-VAVSKVLHLEGEVNKIKSALLSTNKAVVSLSNGVS-NH2 119 124 Ac-AVSKVLHLEGEVNKIKSALLSTNKAVVSLSNGVSV-NH2 120 125 Ac-VSKVLHLEGEVNKIKSALLSTNKAVVSLSNGVSVL-NH2 121 126 Ac-SKVLHLEGEVNKIKSALLSTNKAVVSLSNGVSVLT-NH2 122 127 Ac-KVLHLEGEVNKIKSALLSTNKAVVSLSNGVSVLTS-NH2 123 128 Ac-VLHLEGEVNKIKSALLSTNKAVVSLSNGVSVLTSK-NH2 124 129 Ac-LHLEGEVNKIKSALLSTNKAVVSLSNGVSVLTSKV-NH2 125 130 Ac-HLEGEVNKIKSALLSTNKAVVSLSNGVSVLTSKVL-NH2 126 131 Ac-LEGEVNKIKSALLSTNKAVVSLSNGVSVLTSKVLD-NH2 127 132 Ac-EGEVNKIKSALLSTNKAVVSLSNGVSVLTSKVLDL-NH2 128 133 Ac-GEVNKIKSALLSTNKAVVSLSNGVSVLTSKVLDLK-NH2 129 134 Ac-EVNKIKSALLSTNKAVVSLSNGVSVLTSKVLDLKN-NH2 130 135 Ac-VNKIKSALLSTNKAVVSLSNGVSVLTSKVLDLKNY-NH2 131 136 Ac-NKIKSALLSTNKAVVSLSNGVSVLTSKVLDLKNYI-NH2 132 137 Ac-KIKSALLSTNKAVVSLSNGVSVLTSKVLDLKNYID-NH2 133 138 Ac-IKSALLSTNKAVVSLSNGVSVLTSKVLDLKNYIDK-NH2 134 139 Ac-KSALLSTNKAVVSLSNGVSVLTSKVLDLKNYIDKQ-NH2 135 140 Ac-SALLSTNKAVVSLSNGVSVLTSKVLDLKNYIDKQL-NH2 136 141 Ac-ALLSTNKAVVSLSNGVSVLTSKVLDLKNYIDKQLL-NH2 137 142 Ac-YTSVITIELSNIKENKCNGTDAKVKLIKQELDKYK-NH2 138 143 Ac-TSVITIELSNIKENKCNGTDAKVKLIKQELDKYKN-NH2 139 144 Ac-SVITIELSNIKENKCNGTDAKVKLIKQELDKYKNA-NH2 140 145 Ac-VITIELSNIKENKCNGTDAKVKLIKQELDKYKNAV-NH2 141 146 Ac-ITIELSNIKENKCNGTDAKVKLIKQELDKYKNAVT-NH2 142 147 Ac-TIELSNIKENKCNGTDAKVKLIKQELDKYKNAVTE-NH2 143 148 Ac-IELSNIKENKCNGTDAKVKLIKQELDKYKNAVTEL-NH2 144 149 Ac-ELSNIKENKCNGTDAKVKLIKQELDKYKNAVTELQ-NH2 145 150 Ac-LSNIKENKCNGTDAKVKLIKQELDKYKNAVTELQL-NH2 146 151 Ac-SNIKENKCNGTDAKVKLIKQELDKYKNAVTELQLL-NH2 147 152 Ac-NIKENKCNGTDAKVKLIKQELDKYKNAVTELQLLM-NH2 148 153 Ac-IKENKCNGTDAKVKLIKQELDKYKNAVTELQLLMQ-NH2 149 154 Ac-KENKCNGTDAKVKLIKQELDKYKNAVTELQLLMQS-NH2 150 155 Ac-ENKCNGTDAKVKLIKQELDKYKNAVTELQLLMQST-NH2 151 156 Ac-LLDNFESTWEQSKELWELQEISIQNLHKSALQEYWN-NH2 152 157 Ac-ALGVATSAQITAAVALVEAKQARSDIEKLKEAIRD-NH2 153 158 Ac-LGVATSAQITAAVALVEAKQARSDIEKLKEAIRDT-NH2 154 159 Ac-GVATSAQITAAVALVEAKQARSDIEKLKEAIRDTN-NH2 155 160 Ac-VATSAQITAAVALVEAKQARSDIEKLKEAIRDTNK-NH2 156 161 Ac-ATSAQITAAVALVEAKQARSDIEKLKEAIRDTNKA-NH2 157 162 Ac-TSAQITAAVALVEAKQARSDIEKLKEAIRDTNKAV-NH2 158 163 Ac-SAQITAAVALVEAKQARSDIEKLKEAIRDTNKAVQ-NH2 159 164 Ac-AQITAAVALVEAKQARSDIEKLKEAIRDTNKAVQS-NH2 160 165 Ac-QITAAVALVEAKQARSDIEKLKEAIRDTNKAVQSV-NH2 161 166 Ac-ITAAVALVEAKQARSDIEKLKEAIRDTNKAVQSVQ-NH2 162 167 Ac-TAAVALVEAKQARSDIEKLKEAIRDTNKAVQSVQS-NH2 163 168 Ac-AAVALVEAKQARSDIEKLKEAIRDTNKAVQSVQSS-NH2 164 169 Ac-AVALVEAKQARSDIEKLKEAIRDTNKAVQSVQSSI-NH2 165 170 Ac-VALVEAKQARSDIEKLKEAIRDTNKAVQSVQSSIG-NH2 166 171 Ac-ALVEAKQARSDIEKLKEAIRDTNKAVQSVQSSIGN-NH2 167 172 Ac-LVEAKQARSDIEKLKEAIRDTNKAVQSVQSSIGNL-NH2 168 173 Ac-VEAKQARSDIEKLKEAIRDTNKAVQSVQSSIGNLI-NH2 169 174 Ac-EAKQARSDIEKLKEAIRDTNKAVQSVQSSIGNLIV-NH2 170 175 Ac-KQARSDIEKLKEAIRDTNKAVQSVQSSIGNLIVAI-NH2 171 176 Ac-QARSDIEKLKEAIRDTNKAVQSVQSSIGNLIVAIK-NH2 173 177 Ac-ARSDIEKLKEAIRDTNKAVQSVQSSIGNLIVAIKS-NH2 174 178 Ac-RSDIEKLKEAIRDTNKAVQSVQSSIGNLIVAIKSV-NH2 175 179 Ac-SDIEKLKEAIRDTNKAVQSVQSSIGNLIVAIKSVQ-NH2 176 180 Ac-DIEKLKEAIRDTNKAVQSVQSSIGNLIVAIKSVQD-NH2 177 181 Ac-IEKLKEAIRDTNKAVQSVQSSIGNLIVAIKSVQDY-NH2 178 182 Ac-EKLKEAIRDTNKAVQSVQSSIGNLIVAIKSVQDYV-NH2 179 183 Ac-KLKEAIRDTNKAVQSVQSSIGNLIVAIKSVQDYVN-NH2 180 184 Ac-LKEAIRDTNKAVQSVQSSIGNLIVAIKSVQDYVNK-NH2 181 185 Ac-KEAIRDTNKAVQSVQSSIGNLIVAIKSVQDYVNKE-NH2 182 186 Ac-EAIRDTNKAVQSVQSSIGNLIVAIKSVQDYVNKEI-NH2 183 187 Ac-AIRDTNKAVQSVQSSIGNLIVAIKSVQDYVNKEIV-NH2 184 188 Ac-IRDTNKAVQSVQSSIGNLIVAIKSVQDYVNKEIV-NH2 185 189 Ac-YTPNDITLNNSVALDPIDISIELNKAKSDLEESKE-NH2 186 190 Ac-TPNDITLNNSVALDPIDISIELNKAKSDLEESKEW-NH2 187 191 Ac-PNDITLNNSVALDPIDISIELNKAKSDLEESKEWI-NH2 188 192 Ac-NDITLNNSVALDPIDISIELNKAKSDLEESKEWIR-NH2 189 193 Ac-DITLNNSVALDPIDISIELNKAKSDLEESKEWIRR-NH2 190 194 Ac-ITLNNSVALDPIDISIELNKAKSDLEESKEWIRRS-NH2 191 195 Ac-TLNNSVALDPIDISIELNKAKSDLEESKEWIRRSN-NH2 192 196 Ac-LNNSVALDPIDISIELNKAKSDLEESKEWIRRSNQ-NH2 193 197 Ac-NNSVALDPIDISIELNKAKSDLEESKEWIRRSNQK-NH2 194 198 Ac-NSVALDPIDISIELNKAKSDLEESKEWIRRSNQKL-NH2 195 200 Ac-SVALDPIDISIELNKAKSDLEESKEWIRRSNQKLD-NH2 196 201 Ac-VALDPIDISIELNKAKSDLEESKEWIRRSNQKLDS-NH2 197 202 Ac-ALDPIDISIELNKAKSDLEESKEWIRRSNQKLDSI-NH2 198 203 Ac-LDPIDISIELNKAKSDLEESKEWIRRSNQKLDSIG-NH2 199 204 Ac-DPIDISIELNKAKSDLEESKEWIRRSNQKLDSIGN-NH2 200 205 Ac-PIDISIELNKAKSDLEESKEWIRRSNQKLDSIGNW-NH2 201 206 Ac-IDISIELNKAKSDLEESKEWIRRSNQKLDSIGNWH-NH2 202 207 Ac-DISIELNKAKSDLEESKEWIRRSNQKLDSIGNWHQ-NH2 203 208 Ac-ISIELNKAKSDLEESKEWIRRSNQKLDSIGNWHQS-NH2 204 209 Ac-SIELNKAKSDLEESKEWIRRSNQKLDSIGNWHQSS-NH2 205 210 Ac-IELNKAKSDLEESKEWIRRSNQKLDSIGNWHQSST-NH2 206 211 Ac-ELNKAKSDLEESKEWIRRSNQKLDSIGNWHQSSTT-NH2 207 212 Ac-ELRALRGELRALRGELRALRGELRALRGELRALRGK-NH2 208 213 Ac-YTSLIHSLIEESQNQQQKNEQELLELDKWASLWNWF-NH2 209 214 Ac-YTSLIHSLIEESQNQQEKNEQELLELNKWASLWNWF-NH2 210 215 Ac-YTSLIHSLIEQSQNQQEKNEQELLELDKWASLWNWF-NH2 211 216 Ac-YTSLIHSLIQESQNQQEKNEQELLELDKWASLWNWF-NH2 212 217 Ac-YTSLIHSLIQQSQNQQQKNQQQLLQLNKWASLWNWF-NH2 213 218 Ac-EQELLELDKWASLWNWF-NH2 214 219 Ac-QELLELDKWASLWNWF-NH2 215 220 Ac-ELLELDKWASLWNWF-NH2 216 221 Ac-LELDKWASLWNWF-NH2 218 222 Ac-ELDKWASLWNWF-NH2 219 226 Ac-WASLWNWF-NH2 223 227 Ac-ASLWNWF-NH2 224 229 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASLANAA-NH2 226 230 Ac-YTSLIHSLIEESQNQQEKNEQQLLELDKWASLWNWF-NH2 227 231 Ac-YTSLIQSLIEESQNQQEKNQQELLELDKWASLWNWF-NH2 228 234 Ac-EAAAREAAAREAAARLELDKWASLWNWF-NH2 231 236 Ac-PSLRDPISAEISIQALSYALGGDINKVLEKLGYSG-NH2 233 237 Ac-SLRDPISAEISIQALSYALGGDINKVLEKLGYSGG-NH2 234 238 Ac-LRDPISAEISIQALSYALGGDINKVLEKLGYSGGD-NH2 235 239 Ac-RDPISAEISIQALSYALGGDINKVLEKLGYSGGDL-NH2 236 240 Ac-DPISAEISIQALSYALGGDINKVLEKLGYSGGDLL-NH2 237 241 Ac-PISAEISIQALSYALGGDINKVLEKLGYSGGDLLG-NH2 238 242 Ac-ISAEISIQALSYALGGDINKVLEKLGYSGGDLLGI-NH2 239 243 Ac-SAEISIQALSYALGGDINKVLEKLGYSGGDLLGIL-NH2 240 244 Ac-AEISIQALSYALGGDINKVLEKLGYSGGDLLGILE-NH2 241 245 Ac-EISIQALSYALGGDINKVLEKLGYSGGDLLGILES-NH2 242 246 Ac-ISIQALSYALGGDINKVLEKLGYSGGDLLGILESR-NH2 243 247 Ac-SIQALSYALGGDINKVLEKLGYSGGDLLGILESRG-NH2 244 248 Ac-IQALSYALGGDINKVLEKLGYSGGDLLGILESRGI-NH2 245 249 Ac-QALSYALGGDINKVLEKLGYSGGDLLGILESRGIK-NH2 246 250 Ac-ALSYALGGDINKVLEKLGYSGGDLLGILESRGIKA-NH2 247 251 Ac-LSYALGGDINKVLEKLGYSGGDLLGILESRGIKAR-NH2 248 252 Ac-PDAVYLHRIDLGPPTSLERLDVGTNLGNAIAKLED-NH2 249 253 Ac-DAVYLHRIDLGPPISLERLDVGTNLGNAIAKLEDA-NH2 250 254 Ac-AVYLHRIDLGPPISLERLDVGTNLGNAIAKLEDAK-NH2 251 255 Ac-VYLHRIDLGPPISLERLDVGTNLGNAIAKLEDAKE-NH2 252 256 Ac-YLHRIDLGPPISLERLDVGTNLGNAIAKLEDAKEL-NH2 253 257 Ac-LHRIDLGPPISLERLDVGTNLGNAIAKLEDAKELL-NH2 254 258 Ac-HRIDLGPPISLERLDVGTNLGNAIAKLEDAKELLE-NH2 255 259 Ac-RIDLGPPISLERLDVGTNLGNAIAKLEDAKELLES-NH2 256 260 Ac-IDLGPPISLERLDVGTNLGNAIAKLEDAKELLESS-NH2 257 261 Ac-DLGPPISLERLDVGTNLGNAIAKLEDAKELLESSD-NH2 258 262 Ac-LGPPISLERLDVGTNLGNAIAKLEDAKELLESSDQ-NH2 259 263 Ac-GPPISLERLDVGTNLGNAIAKLEDAKELLESSDQI-NH2 260 264 Ac-PPISLERLDVGTNLGNAIAKLEDAKELLESSDQIL-NH2 261 265 Ac-PISLERLDVGTNLGNAIAKLEDAKELLESSDQILR-NH2 262 266 Ac-ISLERLDVGTNLGNAIAKLEDAKELLESSDQIRS-NH2 263 267 Ac-SLERLDVGTNLGNAIAKLEDAKELLESSDQILRSM-NH2 264 268 Ac-LERLDVGTNLGNAIAKLEDAKELLESSDQILRSMK-NH2 265 269 Ac-EWIRRSNQKLDSI-NH2 266 270 Ac-LELDKWASLANAF-NH2 267 271 Ac-LELDKWASLFNFF-NH2 268 272 Ac-LELDKWASLANWF-NH2 269 273 Ac-LELDKWASLWNAF-NH2 270 274 Ac-ELGNVNNSISNALDKLEESNSKLDKVNVKLTSTSA-NH2 271 275 Ac-TELGNVNNSISNALDKLEESNSKLDKVNVKLTSTS-NH2 282 276 Ac-STELGNVNNSISNALDKLEESNSKLDKVNVKLTST-NH2 273 277 Ac-ISTELGNVNNSISNALDKLEESNSKLDKVNVKLTS-NH2 274 278 Ac-DISTELGNVNNSISNALDKLEESNSKLDKVNVKLT-NH2 275 279 Ac-LDISTELGNVNNSISNALDKLEESNSKLDKVNVKL-NH2 276 280 Ac-NLDISTELGNVNNSISNALDKLEESNSKLDKVNVK-NH2 277 281 Ac-GNLDISTELGNVNNSISNALDKLEESNSKLDKVNV-NH2 278 282 Ac-TGNLDISTELGNVNNSISNALDKLEESNSKLDKVN-NH2 279 283 Ac-VTGNLDISTELGNVNNSISNALDKLEESNSKLDKV-NH2 280 284 Ac-IVTGNLDISTELGNVNNSISNALDKLEESNSKLDK-NH2 281 285 Ac-VIVTGNLDISTELGNVNNSISNALDKLEESNSKLD-NH2 282 286 Ac-QVIVTGNLDISTELGNVNNSISNALDKLEESNSKL-NH2 283 287 Ac-SQVIVTGNLDISTELGNVNNSISNALDKLEESNSK-NH2 284 288 Ac-DSQVIVTGNLDISTELGNVNNSISNALDKLEESNS-NH2 285 289 Ac-LDSQVIVTGNLDISTELGNVNNSISNALDKLEESN-NH2 286 290 Ac-ILDSQVIVTGNLDISTELGNVNNSISNALDKLEES-NH2 287 291 Ac-SILDSQVIVTGNLDISTELGNVNNSISNALDKLEE-NH2 288 292 Ac-ISILDSQVIVTGNLDISTELGNVNNSISNALDKLE-NH2 289 293 Ac-NISILDSQVIVTGNLDISTELGNVNNSISNALDKL-NH2 290 294 Ac-KNISILDSQVIVTGNLDISTELGNVNNSISNALDK-NH2 291 295 Ac-QKNISILDSQVIVTGNLDISTELGNVNNSISNALD-NH2 292 296 Ac-YQKNISILDSQVTVTGNLDISTELGNVNNSISNAL-NH2 293 297 Ac-TYQKNISILDSQVIVTGNLDISTELGNVNNSISNA-NH2 294 298 Ac-ATYQKNISILDSQVIVTGNLDISTELGNVNNSISN-NH2 295 299 Ac-DATYQKNISILDSQVIVTGNLDISTELGNVNNSIS-NH2 296 300 Ac-FDATYQKNISILDSQVIVTGNLDISTELGNVNNSI-NH2 297 301 Ac-EFDATYQKNISILDSQVIVTGNLDISTELGNVNNS-NH2 298 302 Ac-GEFDATYQKNISILDSQVIVTGNLDISTELGNVNN-NH2 299 303 Ac-SGEFDATYQKNISILDSQVIVTGNLDISTELGNVN-NH2 300 304 Ac-LSGEFDATYQKNISILDSQVIVTGNLDISTELGNV-NH2 301 305 Ac-RLSGEFDATYQKNISILDSQVIVTGNLDISTELGN-NH2 302 306 Ac-LRLSGEFDATYQKNISILDSQVIVTGNLDISTELG-NH2 303 307 Ac-TLRLSGEFDATYQKNISILDSQVIVTGNLDISTEL-NH2 304 308 Ac-ITLRLSGEFDATYQKNISILDSQVIVTGNLDISTE-NH2 305 309 Ac-GITLRLSGEFDATYQKNISILDSQVIVTGNLDIST-NH2 306 310 Ac-TATIEAVHEVTDGLSQLAVAVGKMQQFVNDQFNNT-NH2 307 311 Ac-ITATIEAVHEVTDGLSQLAVAVGKMQQFVNDQFNN-NH2 308 312 Ac-SITATIEAVHEVTDGLSQLAVAVGKMQQFVNDQFN-NH2 309 314 Ac-KESITATIEAVHEVTDGLSQLAVAVGKMQQFVNDQ-NH2 310 315 Ac-LKESITATIEAVHEVTDGLSQLAVAVGKMQQFVND-NH2 311 316 Ac-RLKESITATIEAVHEVTDGLSQLAVAVGKMQQFVN-NH2 312 317 Ac-LRLKESITATIEAVHEVTDGLSQLAVAVGKMQQFV-NH2 313 318 Ac-ILRLKESITATIEAVHEVTDGLSQLAVAVGKMQQF-NH2 314 319 Ac-NILRLKESITATIEAVHEVTDGLSQLAVAVGKMQQ-NH2 315 320 Ac-ANILRLKESITATIEAVHEVTDGLSQLAVAVGKMQ-NH2 316 321 Ac-AANILRLKESITATIEAVHEVTDGLSQLAVAVGKM-NH2 317 322 Ac-HKCDDECMNSVKNGTYDYPKYEEESKLNRNFIKGV-NH2 318 323 Ac-KCDDECMNSVKNGTYDYPKYEEESKLNRNEIKGVK-NH2 319 324 Ac-CDDECMNSVKNGTYDYPKYEEESKLNRNEIKGVKL-NH2 320 325 Ac-DDECMNSVKNGTYDYPKYEEESKLNRNEIKGVKLS-NH2 321 326 Ac-DECMNSVKNGTYDYPKYEEESKLNRNEIKGVKLSS-NH2 322 327 Ac-ECMNSVKNGTYDYPKYEEESKLNRNEIKGVKLSSM-NH2 323 328 Ac-CMNSVKNGTYDYPKYEEESKLNRNEIKGVKLSSMG-NH2 324 329 Ac-MNSVKNGTYDYPKYEEESKLNRNEIKGVKLSSMGV-NH2 325 330 Ac-NSVKNGTYDYPKYEEESKLNRNEIKGVKLSSMGVY-NH2 326 331 Ac-SVKNGTYDYPKYEEESKLNRNEIKGVKLSSMGVYQ-NH2 327 332 Ac-VKNGTYDYPKYEEESKLNRNEIKGVKLSSMGVYQI-NH2 328 333 Ac-KNGTYDYPKYEEESKLNRNEIKGVKLSSMGVYQIL-NH2 329 334 Ac-AFIRKSDELLHNV-NH2 330 335 Ac-VVLAGAALGVATAAQITAGIALHQSMLNSQAIDNL-NH2 331 336 Ac-VLAGAALGVATAAQITAGIALHQSMLNSQAIDNLR-NH2 332 337 Ac-LAGAALGVATAAQITAGIALHQSMLNSQAIDNLRA-NH2 333 338 Ac-AGAALGVATAAQITAGIALHQSMLNSQAIDNLRAS-NH2 334 339 Ac-GAALGVATAAQITAGIALHQSMLNSQAIDNLRASL-NH2 335 340 Ac-AALGVATAAQITAGIALHQSMLNSQAIDNLRASLE-NH2 336 341 Ac-ALGVATAAQITAGIALHQSMLNSQAIDNLRASLET-NH2 337 342 Ac-LGVATAAQITAGIALHQSMLNSQAIDNLRASLETT-NH2 338 343 Ac-GVATAAQITAGIALHQSMLNSQAIDNLRASLETTN-NH2 339 344 Ac-VATAAQITAGIALHQSMLNSQAIDNLRASLETTNQ-NH2 340 345 Ac-ATAAQITAGIALHQSMLNSQAIDNLRASLETTNQA-NH2 341 346 Ac-TAAQITAGIALHQSMLNSQAIDNLRASLETTNQAI-NH2 342 347 Ac-AAQITAGIALHQSMLNSQAIDNLRASLETTNQAIE-NH2 343 348 Ac-AQITAGIALHQSMLNSQAIDNLRASLETTNQAIEA-NH2 344 349 Ac-QITAGIALHQSMLNSQAIDNLRASLETTNQAIEAI-NH2 345 350 Ac-ITAGIALHQSMLNSQAIDNLRASLETTNQAIEAIR-NH2 346 351 Ac-TAGIALHQSMLNSQAIDNLRASLETTNQAIEAIRQ-NH2 347 352 Ac-AGIALHQSMLNSQAIDNLRASLETTNQAIEAIRQA-NH2 348 353 Ac-GIALHQSMLNSQAIDNLRASLETTNQAIEAIRQAG-NH2 349 354 Ac-IALHQSMLNSQAIDNLRASLETTNQAIEAIRQAGQ-NH2 350 355 Ac-ALHQSMLNSQAIDNLRASLETTNQAIEAIRQAGQE-NH2 351 356 Ac-LHQSMLNSQAIDNLRASLETTNQAIEAIRQAGQEM-NH2 352 357 Ac-HQSMLNSQAIDNLRASLETTNQAIEAIRQAGQEMI-NH2 353 358 Ac-QSMLNSQAIDNLRASLETTNQAIEAIRQAGQEMIL-NH2 354 359 Ac-SMLNSQAIDNLRASLETTNQAIEAIRQAGQEMILA-NH2 355 360 Ac-MLNSQAIDNLRASLETTNQAIEAIRQAGQEMILAV-NH2 356 361 Ac-LNSQAIDNLRASLETTNQAIEAIRQAGQEMILAVQ-NH2 357 362 Ac-NSQAIDNLRASLETTNQAIEAIRQAGQEMILAVQG-NH2 358 363 Ac-SQAIDNLRASLETTNQAIEAIRQAGQEMILAVQGV-NH2 359 364 Ac-QAIDNLRASLETTNQAIEAIRQAGQEMILAVQGVQ-NH2 360 365 Ac-AIDNLRASLETTNQAIEAIRQAGQEMILAVQGVQD-NH2 361 366 Ac-IDNLRASLETTNQAIEAIRQAGQEMILAVQGVQDY-NH2 362 367 Ac-DNLRASLETTNQAIEAIRQAGQEMILAVQGVQDYI-NH2 363 368 Ac-NLRASLETTNQAIEAIRQAGQEMILAVQGVQDYIN-NH2 364 369 Ac-LRASLETTNQAIEAIRQAGQEMILAVQGVQDYINN-NH2 365 370 Ac-RASLETTNQAIEAIRQAGQEMILAVQGVQDYINNE-NH2 366 371 Ac-YTSVITIELSNIKENKUNGTDAVKLIKQELDKYK-NH2 1519 372 Ac-TSVITIELSNIKENKUNGTDAVKLIKQELDKYKN-NH2 1520 373 Ac-SVITIELSNIKENKUNGTDAVKLIKQELDKYKNA-NH2 1521 374 Ac-SNIKENKUNGTDAKVKLIKQELDKYKNAVTELQLL-NH2 1522 375 Ac-KENKUNGTDAKVKLIKQELDKYKNAVTELQLLMQS-NH2 1523 376 Ac-CLELDKWASLWNWFC-NH2 372 377 Ac-CLELDKWASLANWFC-NH2 373 378 Ac-CLELDKWASLFNFFC-NH2 374 379 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASLFNFF-NH2 375 381 Ac-RMKQLEDKVEELLSKNYHLENELELDKWASLWNWF-NH2 376 382 Ac-KVEELLSKNYHLENELELDKWASLWNWF-NH2 377 383 Ac-RMKQLEDKVEELLSKLEWIRRSNQKLDSI-NH2 378 384 Ac-RMKQLEDKVEELLSKLAFIRKSDELLHNV-NH2 379 385 Ac-ELEALRGELRALRGELELDKWASLWNWF-NH2 380 386 Ac-LDPIDISIELNKAKSDLEESKEWIRRSNQKLDSI-NH2 381 387 Ac-CNEQLSDSFPVEFFQV-NH2 382 388 Ac-MAEDDPYLGRPEQMFHLDPSL-NH2 383 389 Ac-EDFSSIADMDFSALLSQISS-NH2 384 390 Ac-TWQEWERKVDFLEENITALLEEAQIQQEKNMYELQ-NH2 385 391 Ac-WQEWERKVDFLEENITALLEEAQIQQEKNMYELQK-NH2 386 392 Ac-QEWERKVDFLEENITALLEEAQIQQEKNMYELQKL-NH2 387 393 Ac-EWERKVDFLEENITALLEEAQIQQEKNMYELQKLN-NH2 388 394 Ac-WERKVDFLEENITALLEEAQIQQEKNMYELQKLNS-NH2 389 395 Ac-ERKVDFLEENITALLEEAQIQQEKNMYELQKLNSW-NH2 390 396 Ac-RKVDFLEENITALLEEAQIQQEKNMYELQKLNSWD-NH2 391 397 Ac-KVDFLEENITALLEEAQIQQEKNMYELQKLNSWDV-NH2 392 398 Ac-VDFLEENITALLEEAQIQQEKNMYELQKLNSWDVF-NH2 393 399 Ac-DFLEENITALLEEAQIQQEKNMYELQKLNSWDVFG-NH2 394 400 Ac-FLEENITALLEEAQIQQEKNMYELQKLNSWDVFGN-NH2 395 401 Ac-LEENITALLEEAQIQQEKNMYELQKLNSWDVFGNW-NH2 396 402 Ac-LEENITALLEEAQIQQEKNMYELQKLNSWDVFGNWF-NH2 397 403 Ac-NEQSEEKENELYWAKEQLLDLLFNIFNQTVGAWIMQ-NH2 398 405 Ac-QQQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKYLKD-NH2 400 406 Ac-QQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKYLKDQ-NH2 401 407 Ac-QQLLDVVKRQQELLRLTVWGPKNLQTRVTAIEKYLKDQ-NH2 402 408 Ac-DERKQDKVLVVQQTGTLQLTLIQLEKTAKLQWVRLNRY-NH2 403 409 Ac-QQQLLDVVKRQQELLPLTVWGTKNLQTRVTAIEKY-NH2 404 410 Ac-QQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKYL-NH2 405 411 Ac-QLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKYLK-NH2 406 412 Ac-LLDVVKRQQELLRLTVWGTKNLQTRVTAIEKYLKD-NH2 407 413 Ac-LDVVKRQQELLRLTVWGTKNLQTRVTAIEKYLKDQ-NH2 408 414 Ac-DVVKRQQELLRLTVWGTKNLQTRVTAIEKYLKDQA-NH2 409 415 Ac-VVKRQQELLRLTVWGTKNLQTRVTAIEKYLKDQAQ-NH2 410 416 Ac-VKRQQELLRLTVWGTKNLQTRVTAIEKYLKDQAQL-NH2 411 417 Ac-KRQQELLRLTVWGTKNLQTRVTAIEKYLKDQAQLN-NH2 412 418 Ac-RQQELLRLTVWGTKNLQTRVTAIEKYLKDQAQLNA-NH2 413 419 Ac-QQELLRLTVWGTKNLQTRVTAIEKYLKDQAQLNAW-NH2 414 420 Ac-QELLRLTVWGTKNLQTRVTAIEKYLKDQAQLNAWG-NH2 415 421 Ac-ELLRLTVWGTKNLQTRVTAIEKYLKDQAQLNAWGC-NH2 416 422 Ac-NNLLRAIEAQQHLLQLTVWGPKQLQARILAVERYLKDQ-NH2 417 423 Ac-SELEIKRYKNRVASRKCRAKFKQLLQHYREVAAAK-NH2 418 424 Ac-ELEIKRYKNRVASRKCRAKFKQLLQHYREVAAAKS-NH2 419 425 Ac-LEIKRYKNRVASRKCRAKFKQLLQHYREVAAAKSS-NH2 420 426 Ac-EIKRYKNRVASRKCRAKFKQLLQHYREVAAAKSSE-NH2 421 427 Ac-IKRYKNRVASRKCRAKFKQLLQHYREVAAAKSSEN-NH2 422 428 Ac-KRYKNRVASRKCRAKFKQLLQHYREVAAAKSSEND-NH2 423 429 Ac-RYKNRVASRKCRAKFKQLLQHYREVAAAKSSENDR-NH2 424 430 Ac-YKNRVASRKCRAKFKQLLQHYREVAAAKSSENDRL-NH2 425 431 Ac-KNRVASRKCRAKFKQLLQHYREVAAAKSSENDRLR-NH2 426 432 Ac-NRVASRKCRAKFKQLLQHYREVAAAKSSENDRLRL-NH2 427 433 Ac-RVASRKCRAKFKQLLQHYREVAAAKSSENDRLRLL-NH2 428 434 Ac-VASRKCRAKFKQLLQHYRLVAAAKSSENDRLRLLL-NH2 429 435 Ac-ASRKCRAKFKQLLQHYREVAAAKSSENDRLRLLLK-NH2 430 436 Ac-SRKCRAKFKQLLQHYREVAAAKSSENDRLRLLLKQ-NH2 431 437 Ac-RKCRAKFKQLLQHYREVAAAKSSENDRLRLLLKQM-NH2 432 438 Ac-KCRAKFKQLLQHYREVAAAKSSENDRLRLLLKQMC-NH2 433 439 Ac-CRAKFKQLLQHYREVAAAKSSENDRLRLLLKQMCP-NH2 434 440 Ac-RAKFKQLLQHYREVAAAKSSENDRLRLLLKQMCPS-NH2 435 441 Ac-AKFKQLLQHYREVAAAKSSENDRLRLLLKQMCPSLNH2 436 442 Ac-KFKQLLQHYREVAAAKSSENDRLRLLLKQMCPSLD-NH2 437 443 Ac-FKQLLQHYREVAAAKSSENDRLRLLLKQMCPSLDV-NH2 438 444 Ac-KQLLQHYREVAAAKSSENDRLRLLLKQMCPSLDVD-NH2 439 445 Ac-QLLQHYREVAAAKSSENDRLRLLLKQMCPSLDVDS-NH2 440 446 Ac-LLQHYREVAAAKSSENDRLRLLLKQMCPSLDVDSI-NH2 441 447 Ac-LQHYREVAAAKSSENDRLRLLLKQMCPSLDVDSII-NH2 442 448 Ac-QHYREVAAAKSSENDRLRLLLKQMCPSLDVDSIIP-NH2 443 449 Ac-HYREVAAAKSSENDRLRLLLKQMCPSLDVDSIIPR-NH2 444 450 Ac-YREVAAAKSSENDRLRLLLKQMCPSLDVDSIIPRT-NH2 445 451 Ac-REVAAAKSSENDRLRLLLKQMCPSLDVDSIIPRTP-NH2 446 452 Ac-EVAAAKSSENDRLRLLLKQMCPSLDVDSIIPRTPD-NH2 447 453 Ac-VAAAKSSENDRLRLLLKQMCPSLDVDSIIPRTPDV-NH2 448 454 Ac-AAAKSSENDRLRLLLKQMCPSLDVDSIIPRTPDVL-NH2 449 455 Ac-AAKSSENDRLRLLLKQMCPSLDVDSIIPRTPDVLH-NH2 450 456 Ac-AKSSENDRLRLLLKQMCPSLDVDSIIPRTPDVLHE-NH2 451 457 Ac-KSSENDRLRLLLKQMCPSLDVDSIIPRTPDVLHED-NH2 452 458 Ac-SSFNDRLRLLLKQMCPSLDVDSIIPRTPDVLHEDL-NH2 453 459 Ac-SENDRLRLLLKQMCPSLDVDSIIPRTPDVLHEDLL-NH2 454 460 Ac-ENDRLRLLLKQMCPSLDVDSIIPRTPDVLHEDLLN-NH2 455 461 Ac-NDRLRLLLKQMCPSLDVDSIIPRTPDVLHEDLLNF-NH2 456 534 Ac-PGYRWMCLRRFIIFLFILLLCLIFLLVLLDYQGML-NH2 458 535 Ac-GYRWMCLRRFIIFLFILLLCLIFLLVLLDYQGMLP-NH2 459 536 Ac-YRWMCLRRFIIFLFILLLCLIFLLVLLDYQGMLPV-NH2 460 537 Ac-RWMCLRRFIIFLFILLLCLIFLLVLLDYQGMLPVC-NH2 461 538 Ac-WMCLRRFIIFLFILLLCLIFLLVLLDYQGMLPVCP-NH2 462 539 Ac-MCLRRFIIFLFILLLCLIFLLVLLDYQGMLPVCPL-NH2 463 540 Ac-CLRRFIIFLFILLLCLIFLLVLLDYQGMLPVCPLI-NH2 464 541 Ac-LRRFIIFLFILLLCLIFLLVLLDYQGMLPVCPLIP-NH2 465 542 Ac-RRFIIFLFILLLCLIFLLVLLDYQGMLPVCPLIPG-NH2 466 543 Ac-RFIIFLFILLLCLIFLLVLLDYQGMLPVCPLIPGS-NH2 467 544 Ac-FIIFLFILLLCLIFLLVLLDYQGMLPVCPLIPGSS-NH2 468 545 Ac-IIFLFILLLCLIFLLVLLDYQGMLPVCPLIPGSST-NH2 469 546 Ac-IFLFILLLCLIFLLVLLDYQGMLPVCPLIPGSSTT-NH2 470 547 Ac-FLFILLLCLIFLLVLLDYQGMLPVCPLIPGSSTTS-NH2 471 548 Ac-LFILLLCLIFLLVLLDYQGMLPVCPLIPGSSTTST-NH2 472 549 Ac-FILLLCLIFLLVLLDYQGMLPVCPLIPGSSTTSTG-NH2 473 550 Ac-ILLLCLIFLLVLLDYQGMLPVCPLIPGSSTTSTGP-NH2 474 551 Ac-LLLCLIFLLVLLDYQGMLPVCPLIPGSSTTSTGPC-NH2 475 552 Ac-LLCLIFLLVLLDYQGMLPVCPLIPGSSTTSTGPCR-NH2 476 553 Ac-LCLIFLLVLLDYQGMLPVCPLIPGSSTTSTGPCRT-NH2 477 554 Ac-CLIFLLVLLDYQGMLPVCPLIPGSSTTSTGPCRTC-NH2 478 555 Ac-LIFLLVLLDYQGMLPVCPLIPGSSTTSTGPCRTCM-NH2 479 556 Ac-IFLLVLLDYQGMLPVCPLIPGSSTTSTGPCRTCMT-NH2 480 557 Ac-FLLVLLDYQGMLPVCPLIPGSSTTSTGPCRTCMTT-NH2 481 558 Ac-PPLVLQAGFFLLTRILTIPQSLDSWWTSLNFLGGT-NH2 1524 559 Ac-LLVLQAGFFLLTRILTIPQSLDSWWTSLNFLGGTT-NH2 483 560 Ac-LVLQAGFFLLTRILTIPQSLDSWWTSLNFLGGTTV-NH2 484 561 Ac-VLQAGFFLLTRILTIPQSLDSWWTSLNFLGGTTVC-NH2 485 562 Ac-LQAGFFLLTRILTIPQSLDSWWTSLNFLGGTTVCL-NH2 486 563 Ac-QAGFFLLTRILTIPQSLDSWWTSLNFLGGTTVCLG-NH2 487 564 Ac-AGFFLLTRILTIPQSLDSWWTSLNFLGGTTVCLGQ-NH2 488 565 Ac-GFFLLTRILTIPQSLDSWWTSLNFLGGTTVCLGQN-NH2 489 566 Ac-FFLLTRILTIPQSLDSWWTSLNFLGGTTVCLGQNS-NH2 490 567 Ac-FLLTRILTIPQSLDSWWTSLNFLGGTTVCLGQNSQ-NH2 491 568 Ac-LLTRILTIPQSLDSWWTSLNFLGGTTVCLGQNSQS-NH2 492 569 Ac-LTRILTIPQSLDSWWTSLNFLGGTTVCLGQNSQSP-NH2 493 570 Ac-FWNWLSAWKDLELKSLLEEVKDELQKMR-NH2 494 571 Ac-NNLLRAIEAQQHLLQLTVW-NH2 495 572 Ac-CGGNNLLRAIEAQQHLLQLTVWGIKQLQARILAVERYLKDQ-NH2 496 573 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 497 574 C13H27CO-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 498 575 Ac-AVSKGYLSALRTGWYTSVITIELSNIKENKLNGTDA-NH2 1525 576 Ac-SISNIETVIEFQQKNNRLLEITREFSVNAGVTTPVS-NH2 500 577 Ac-DQQIKQYKRLLDRLIIPLYDGLRQKDVIVSNQESN-NH2 501 578 Ac-YSELTNIFGDNIGSLQEKGIKLQGIASLYRTNITEI-NH2 502 579 Ac-TSITLQVRLPLLTRLLNTQIYRVDSISYNIQNREWY-NH2 503 580 Ac-VEIAEYRRLLRTVLEPIRDALNAMTQNIRPVQSVA-NH2 504 581 Ac-SYFIVLSIAYPTLSEIKGVIVHRLEGVSYNIGSQEW-NH2 505 582 Ac-LKEAIRDTNKAVQSVQSSIGNLIVAIKS-NH2 506 583 NNLLRAIEAQQHLLQLTVWGIKQLQARILAVERYLKDQ-NH2 507 583 NNLLRAIEAQQHLLQLTVWGIKQLQARILAVERYLKDQ-NH2 507 584 QKQEPIDKELYPLTSL 508 585 YPKFVKQNTLKLAT 509 586 QYIKANQKFIGITE 510 587 NGQIGNDPNRDILY 511 588 AC-RPDVY-OH 512 589 CLELDKWASLWNWFC-(cyclic) 513 590 CLELDKWASLANWFC-(cyclic) 514 591 CLELDKWASLANFFC-(cyclic) 515 594 Ac-NNLLRAIEAQQQHLLQLTVWGIKQLQARILAVERYLKDQ-NH2 516 595 Ac-CGGYTSLIHSLIEESQNQQEKNEQELLELDKWASLWNNWF-NH2 517 596 Ac-PLLVLQAGFFLLTRILTIPQSLDSWWTSLNFLGGT-NH2 518 597 Ac-LLVLQAGFFLLTRILTIPQSLDSWWTSLNFLGGTT-NH2 519 598 Ac-LVLQAGFFLLTRILTIPQSLDSWWTSLNFLGGTTV-NH2 520 599 Ac-VLQAGFFLLTRILTIPQSLDSWWTSLNFLGGTTVC-NH2 521 600 Ac-LQAGFFLLTRILTIPQSLDSWWTSLNFLGGTTVCL-NH2 522 601 Ac-QAGFFLLTRILTIPQSLDSWWTSLNFLGGTTVCLG-NH2 523 602 Ac-AGFFLLTRILTIPQSLDSWWTSLNFLGGTTVCLGQ-NH2 524 603 Ac-GFFLLTRILTIPQSLDSWWTSLNFLGGTTVCLGQN-NH2 525 604 Ac-FFLLTRILTIPQSLDSWWTSLNFLGGTTVCLGQNS-NH2 526 605 Ac-FLLTRILTIPQSLDSWWTSLNFLGGTTVCLGQNSQ-NH2 527 606 Ac-LLTRILTIPQSLDSWWTSLNFLGGTTVCLGQNSQS-NH2 528 607 Ac-LTRILTIPQSLDSWWTSLNFLGGTTVCLGQNSQSP-NH2 529 608 Ac-LELDKWASLWNWA-NH2 530 609 Ac-LELDKWASAWNWF-NH2 531 610 Ac-LELDKAASLWNWF-NH2 532 611 Ac-LKLDKWASLWNWF-NH2 533 612 Ac-LELKKWASLWNWF-NH2 534 613 Ac-DELLHNVNAGKST-NH2 535 614 Ac-KSDELLHNVNAGKST-NH2 536 615 Ac-IRKSDELLHNVNAGKST-NH2 537 616 Ac-AFIRKSDELLHNVNAGKST-NH2 538 617 Ac-FDASISQVNEKINQSLAFI-NH2 539 618 Ac-YAADKESTQKAFDGITNKVNSVIEKMNTQFEAVGKE-NH2 540 619 Ac-SVIEKMNTQFEAVGKEFGNLERRLENLNKRMEDGFL-NH2 541 620 Ac-VWTYNAELLVLMENERTLDFHDSNVKNLYDKVRMQL-NH2 542 621 Ac-EWDREINNYTSLIHSLIEESQNQQEKNEQEGGC-NH2 543 622 Ac-INNYTSLIHSLIEESQNQQEKNEQELLELDKWASL-NH2 544 623 Ac-INNYTSLIHSLIEESQNQQEKNEQELLE-NH2 545 624 Ac-WMEWDREINNYTSLIHSLIEESQNQQEKNEQELLE-NH2 546 625 Ac-MTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 547 626 Ac-IDISIELNKAKSDLEESKEWIKKSNQKLDSIGNWH-NH2 548 627 Ac-NQQEKNEQELLELDKWASLWNWFNITNWLWYIKIFI-NH2 549 627 Ac-NQQEKNEQELLELDKWASLWNWFNITNWLWYIKIFI-NH2 549 628 Ac-QNQQEKNEQELLELDKWASLWNWFNITNWLWYIKIF-NH2 550 629 Ac-SQNQQEKNEQELLELDKWASLWNWFNITNWLWYIKI-NH2 551 630 Ac-ESQNQQEKNEQELLELDKWASLWNWFNITNWLWYIK-NH2 552 631 Ac-EESQNQQEKNEQELLELDKWASLWNWFNITNWLWYI-NH2 553 632 Ac-IEESQNQQEKNEQELLELDKWASLWNWFNITNWLWY-NH2 554 633 Ac-LIEESQNQQEKNEQELLELDKWASLWNWFNITNWLW-NH2 555 634 Ac-SLIEESQNQQEKNEQELLELDKWASLWNWFNITNWL-NH2 556 635 Ac-HSLIEESQNQQEKNEQELLELDKWASLWNWFNITNW-NH2 557 636 Ac-IHSLIEESQNQQEKNEQELLELDKWASLWNWFNITN-NH2 558 637 Ac-LIHSLIEESQNQQEKNEQELLELDKWASLWNWFNIT-NH2 559 638 Ac-SLIHSLIEESQNQQEKNEQELLELDKWASLWNWFNI-NH2 560 639 Ac-TSLIHSLIEESQNQQEKNEQELLELDKWASLWNWFN-NH2 561 640 Ac-NYTSLIHSLIEESQNQQEKNEQELLELDKWASLWNW-NH2 562 641 Ac-NNYTSLIHSLIEESQNQQEKNEQELLELDKWASLWN-NH2 563 642 Ac-INNYTSLIHSLIEESQNQQEKNEQELLELDKWASLW-NH2 564 643 Ac-EINNYTSLIHSLIEESQNQQEKNEQELLELDKWASL-NH2 565 644 Ac-REINNYTSLIHSLIEESQNQQEKNEQELLELDKWAS-NH2 566 645 Ac-DREINNYTSLIHSLIEESQNQQEKNEQELLELDKWA-NH2 567 646 Ac-WDREINNYTSLIHSLIEESQNQQEKNEQELLELDKW-NH2 568 647 Ac-EWDREINNYTSLIHSLIEESQNQQEKNEQELLELDK-NH2 569 648 Ac-MEWDREINNYTSLIHSLIEESQNQQEKNEQELLELD-NH2 570 649 Ac-WMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL-NH2 572 650 Ac-TWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLE-NH2 573 651 Ac-MTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELL-NH2 574 652 Ac-NMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQEL-NH2 575 653 Ac-NNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQE-NH2 576 654 Ac-WNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQ-NH2 577 655 Ac-IWNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNE-NH2 578 656 Ac-QIWNNMTWMEWDREINNYTSLIHSLIEESQNQQEKN-NH2 579 657 Ac-EQIWNNMTWMEWDRENNYTSLIHSLIEESQNQQEK-NH2 580 658 Ac-LEQIWNNMTWMEWDREINNYTSLIHSLIEESQNQQE-NH2 581 659 Ac-SLEQIWNNMTWMEWDREINNYTSLIHSLIEESQNQQ-NH2 582 660 Ac-KSLEQIWNNMTWMEWDREINNYTSLIHSLIEESQNQ-NH2 583 661 Ac-NKSLEQIWNNMTWMEWDREINNYTSLIHSLIEESQN-NH2 584 662 Ac-SLAFIRKSDELLHNVNAGKST-NH2 585 663 Ac-FDASISQVNEKINQSLAFIRK-NH2 586 664 Ac-YTSLIHSLIEESQQQQEKQEQELLELDKWASLWNWF-NH2 587 665 Ac-FDASISQVNEKINQSLAFIRKSDELLHNVNAGK-NH2 588 666 Ac-FDASISQVNEKINQSLAFIRKSDELLHNVNA-NH2 589 667 Ac-FDASISQVNEKINQSLAFIRKSDELLHNV-NH2 590 668 Ac-FDASISQVNEKINQSLAFIRKSDELLH-NH2 591 669 Ac-FDASISQVNEKINQSLAFIRKSDEL-NH2 592 670 Ac-FDASISQVNEKINQSLAFIRKSD-NH2 593 671 Ac-ASISQVNEKINQSLAFIRKSDELLHNVNAGKST-NH2 594 672 Ac-ISQVNEKINQSLAFIRKSDELLHNVNAGKST-NH2 595 673 Ac-QVNEKINQSLAFIRKSDELLHNVNAGKST-NH2 596 674 Ac-NEKINQSLAFIRKSDELLHNVNAGKST-NH2 597 675 Ac-KINQSLAFIRKSDELLHNVNAGKST-NH2 598 676 Ac-NQSLAFIRKSDELLHNVNAGKST-NH2 599 677 Ac-FWNWLSAWKDLELYPGSLELDKWASLWNWF-NH2 600 678 Ac-CGGNNLLRAIEAQQHLLQLTVWGIKQLQARILAVERYLKDQ-NH2 601 679 Ac-CGGYTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 602 680 YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF 603 681 NNLLRAIEAQQHLLQLTVWGIKQLQARILAVERYLKDQ 604 682 Ac-EKNMYELQKLNSWDVFTNWLDFTSWVRYIQYIQYGV-NH2 605 683 Ac-QEKNMYELQKLNSWDVFTNWLDFTSWVRYIQYIQYG-NH2 606 684 Ac-QQEKNMYELQKLNSWDVFTNWLDFTSWVRYIQYIQY-NH2 607 685 Ac-IQQEKNMYELQKLNSWDVFTNWLDFTSWVRYIQYIQ-NH2 608 686 Ac-QIQQEKNMYELQKLNSWDVFTNWLDFTSWVRYIQYI-NH2 609 687 Ac-AQIQQEKNMYELQKLNSWDVFTNWLDFTSWVRYIQY-NH2 610 688 Ac-QAQIQQEKNMYELQKLNSWDVFTNWLDFTSWVRYIQ-NH2 611 689 Ac-EQAQIQQEKNMYELQKLNSWDVFTNWLDFTSWVRYI-NH2 612 690 Ac-LEQAQIQQEKNMYELQKLNSWDVFTNWLDFTSWVRY-NH2 613 691 Ac-SLEQAQIQQEKNMYELQKLNSWDVFTNWLDFTSWVR-NH2 614 692 Ac-QSLEQAQIQQEKNMYELQKLNSWDVFTNWLDFTSWV-NH2 615 693 Ac-SQSLEQAQIQQEKNMYELQKLNSWDVFTNWLDFTSW-NH2 616 694 Ac-ISQSLEQAQIQQEKNMYELQKLNSWDVFTNWLDFTS-NH2 617 695 Ac-NISQSLEQAQIQQEKNMYELQKLNSWDVFTNWLDFT-NH2 618 696 Ac-ANISQSLEQAQIQQEKNMYELQKLNSWDVFTNWLDF-NH2 619 697 Ac-EANISQSLEQAQIQQEKNMYELQKLNSWDVFTNWLD-NH2 620 699 Ac-YLEANISQSLEQAQIQQEKNMYELQKLNSWDVFTNW-NH2 622 700 Ac-YTSLIHSLIEESQNQQEKNEQEL-NH2 623 701 Ac-YTSLIHSLIEESQNLQEKNEQELLELDKWASLWNWF-NH2 624 702 Ac-YTSLIHSLIEESQNQQEKLEQELLELDKWASLWNWF-NH2 625 703 Ac-YTSLIHSLIEESQNQQEKNEQELLEFDKWASLWNWF-NH2 626 704 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKPASLWNWF-NH2 627 705 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASPWNWF-NH2 628 706 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNSF-NH2 629 707 Biotin NH(CH2)4CO-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 705 708 Biotin NH(CH2)6CO-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 630 709 FMOC-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF 497 710 FMOC-NNLLRAIEAQQHLLQLTVWGIKQLQARILAVERYLKDQ 16 711 Ac-EWDREINNYTSLIHSLIEESQNQQEKNEQE-NH2 634 712 Ac-LIEESQNQQEKNEQELLELDKWASLWNWF-NH2 635 713 Ac-FWNWLSAWKDLELGGPGSGPGGLELDKWASLWNWF-NH2 636 714 Ac-LIHSLIEESQNQQEKNEQELLELDKWASL-NH2 637 715 Ac-TSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 638 716 Ac-LIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 639 718 FMOC-GGGGGYTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 640 719 Ac-HSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 641 720 Ac-YTSLIYSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 642 721 Ac-YTSLIHSLIEKSQNQQEKNEQELLELDKWASLWNWF-NH2 643 722 Ac-YTSLIHSSIEESQNQQEKNEQELLELDKWASLWNWF-NH2 644 723 Ac-LEANISQLLEQAQIQQEKNMYELQKLNSWDVFTNWL-NH2 645 724 Ac-SLEECDSELEIKRYKNRVASRKCRAKFKQLLQHYR-NH2 646 725 Ac-LEECDSELEIKRYKNRVASRKCRAKFKQLLQHYRE-NH2 647 726 Ac-EECDSELEIKRYKNRVASRKCRAKFKQLLQHYREV-NH2 648 727 Ac-ECDSELEIKRYKNRVASRKCRAKFKQLLQHYREVA-NH2 649 728 Ac-CDSELEIKRYKNRVASRKCRAKFKQLLQHYREVAA-NH2 650 729 Ac-DSELEIKRYKNRVASRKCRAKFKQLLQHYREVAAA-NH2 651 730 Desaminotyrosine-FDASISQVNEKINQSLAFIRKSDELLHNVNAGKST-NH2 679 731 WASLWNW-NH2 653 732 Ac-EAQQHLLQLTVWGIKQLQARILAVERYLKDQQLLGIWG-NH2 654 733 Ac-IEAQQHLLQLTVWGIKQLQARILAVERYLKDQQLLGIW-NH2 655 734 Ac-AIEAQQHLLQLTVWGIKQLQARILAVERYLKDQQLLGI-NH2 656 735 Ac-RAIEAQQHLLQLTVWGIKQLQARILAVERYLKDQQLLG-NH2 657 736 Ac-LRAIEAQQHLLQLTVWGIKQLQARILAVERYLKDQQLL-NH2 658 737 Ac-LLRAIEAQQHLLQLTVWGIKQLQARILAVERYLKDQQL-NH2 659 738 Ac-NLLRAIEAQQHLLQLTVWGIKQLQARILAVERYLKDQQ-NH2 660 739 Ac-QNNLLRAIEAQQHLLQLTVWGIKQLQARILAVERYLKD-NH2 661 740 Ac-QQNNLLRAIEAQQHLLQLTVWGIKQLQARILAVERYLK-NH2 662 741 Ac-QQQNNLLRAIEAQQHLLQLTVWGIKQLQARILAVERYL-NH2 663 742 Ac-VQQQNNLLRAIEAQQHLLQLTVWGIKQLQARILAVERY-NH2 664 743 Ac-IVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARILAVER-NH2 665 744 Ac-GIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARILAVE-NH2 666 745 Ac-SGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARILAV-NH2 667 758 Ac-RSMTLTVQARQLLSGIVQQQNNLLRAIEAQQHLLQLTV-NH2 668 760 Ac-GARSMTLTVQARQLLSGIVQQQNNLLRAIEAQQHLLQL-NH2 669 764 Ac-GSTMGARSMTLTVQARQLLSGIVQQQNNLLRAIEAQQH-NH2 670 765 Ac-GSTMGARSMTLTVQARQLLSGIVQQQNNLLRAIEAQQH-NH2 671 766 Ac-EGSTMGARSMTLTVQARQLLSGIVQQQNNLLRAIEAQQ-NH2 672 767 Ac-RAKFKQLLQHYREVAAAKSSENDRLRLL-NH2 673 768 Ac-AKFKQLLQHYREVAAAKSSENDRLRLLL-NH2 674 769 Ac-KFKQLLQRYREVAAAKSSENDRLRLLLK-NH2 675 770 Ac-FKQLLQHYREVAAAKSSENDRLRLLLKQ-NH2 676 771 Ac-RAKFKQELQHYREVAAAKSSENDRLRLLLKQMCPS-NH2 677 772 DKWASLWNWF-NH2 678 773 Biotin-FDASISQVNEKINQSLAFIRKSDELLHNVNAGKST-NH2 679 774 Ac-YDASISQVNEKINQSLAFIRKSDELLHNVNAGKST-NH2 680 775 Ac-YDASISQVNEKINQSLAYIRKSDELLHNVNAGKST-NH2 681 776 Ac-FDASISQVNEKINQSLAYIRKSDELLHNVNAGKST-NH2 682 777 Ac-FDASISQVQEKIQQSLAFIRKSDELLHQVQAGKST-NH2 683 778 Ac-FDASISQVNEKINQALAFIRKADELLHNVNAGKST-NH2 684 779 Ac-FDASISQVNEKINQALAFIRKSDELLHNVNAGKST-NH2 685 780 Ac-FDASISQVNEKINQSLAFIRKADELLHNVNAGKST-NH2 686 781 Ac-YDASISQVQEEIQQALAFIRKADELLEQVQAGKST-NH2 687 782 Ac-FDASISQVNEKINQSLAFIRKSDELLENVNAGKST-NH2 688 783 Ac-FDASISQVNEEINQSLAFIRKSDELLHNVNAGKST-NH2 689 784 Ac-VFPSDEFDASISQVNEKINQSLAFIRKSDELLENV-NH2 690 785 Ac-VFPSDEFDASISQVNEEINQSLAFIRKSDELLENV-NH2 691 786 Ac-VYPSDEYDASISQVNEEINQALAYIRKADELLENV-NH2 692 787 Ac-VFPSDEFDASISQVNEEINQSLAFIRKSDELLHNV-NH2 693 788 Ac-SNKSLEQIWNNMTWMEWDREINNYTSLIHSLIEESQ-NH2 694 789 Ac-WSNKSLEQIWNNMTWMEWDREINNYTSLIHSLIEES-NH2 695 790 Ac-SWSNKSLEQIWNNMTWMEWDREINNYTSLIHSLIEE-NH2 696 791 Ac-ASWSNKSLEQIWNNMTWMEWDREINNYTSLIHSLIE-NH2 697 792 Ac-NASWSNKSLEQIWNNMTWMEWDREINNYTSLIHSLI-NH2 698 793 Ac-WNASWSNKSLEQIWNNMTWMEWDREINNYTSLIHSL-NH2 699 793 Ac-WNASWSNKSLEQIWNNMTWMEWDREINNYTSLIHSL-NH2 699 794 Ac-PWNASWSNKSLEQIWNNMTWMEWDREINNYTSLIHS-NH2 700 795 Ac-VPWNASWSNKSLEQIWNNMTWMEWDREINNYTSLIH-NH2 701 796 Ac-AVPWNASWSNKSLEQIWNNMTWMEWDREINNYTSLI-NH2 702 797 Ac-TAVPWNASWSNKSLEQIWNNMTWMEWDREINNYTSL-NH2 703 798 Ac-TTAVPWNASWSNKSLEQIWNNMTWMEWDREINNYTS-NH2 704 800 Ac-AAASDEFDASISQVNEKINQSLAFIRKSDELLHNV-NH2 706 801 Ac-VFFAAAFDASISQVNEKINQSLAFIRKSDELLHNV-NH2 707 802 Ac-VFPSDEAAASISQVNEKINQSLAFIRKSDELLHNV-NH2 708 803 Ac-VFPSDEFDAAAAQVNEKINQSLAFIRKSDELLHNV-NH2 709 804 Ac-VFPSDEFDASISAAAEKINQSLAFIRKSDELLHNV-NH2 710 805 Ac-VFPSDEFDASISQVNAAANQSLAFIRKSDELLHNV-NH2 711 806 Ac-VFPSDEFDASISQVNEKIAAALAFIRKSDELLHNV-NH2 712 807 Ac-VFPSDEFDASISQVNEKINQSAAAIRKSDELLHNV-NH2 713 808 Ac-VFPSDEFDASISQVNEKINQSLAFAAASDELLHNV-NH2 714 809 Ac-VFPSDEFDASISQVNEKINQSLAFIRKAAALLHNV-NH2 715 810 Ac-VFPSDEFDASISQVNEKINQSLAFIRKSDEAAANV-NH2 716 811 Ac-VFPSDEFDASISQVNEKINQSLAFIRKSDELLAAA-NH2 717 812 Ac-VYPSDEFDASISQVNEKINQSLAFIRKSDELLHNV-NH2 718 813 Ac-AAAAIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 719 814 Ac-YTSLIRSLIEESQQQQEKNEQELLELDKWASLWNWF-NH2 720 815 Ac-YTSLIHSLIEESQNQQEKQEQELLELDKWASLWNWF-NH2 721 816 Ac-QIWNNMTWMEWDREINNYTSLIHSLIEESQNQQEKQ-NH2 722 817 Ac-QIWNNMTWMEWDREINNYTSLIHSLIEESQQQQEKN-NH2 723 818 Ac-QIWNNMTWMEWDREINNYTSLIHSLIEESQQQQEKQ-NH2 724 819 Ac-NKSLEQIWNNMTWMEWDREINNYTSLIHSLIEESQQ-NH2 725 820 Ac-FDASISQVNEKINQSLAFIEESDELLHNVNAGKST-NH2 726 821 Ac-ACIRKSDELCL-NH2 727 823 Ac-YTSLIHSLIEESQNQQEKDEQELLELDKWASLWNWF-NH2 728 824 Ac-YTSLIHSLIEESQDQQEKNEQELLELDKWASLWNWF-NH2 729 825 Ac-YTSLIHSLIEESQDQQEKDEQELLELDKWASLWNWF-NH2 730 826 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWDWF-NH2 731 841 Ac-LEANITQSLEQAQIQQEKNMYELQKLNSWDVFTNWL-NH2 732 842 Ac-LEANISASLEQAQIQQEKNMYELQKLNSWDVFTNWL-NH2 733 843 Ac-LEANISALLEQAQIQQEKNMYELQKLNSWDVFTNWL-NH2 734 844 Ac-LEANITALLEQAQIQQEKNMYELQKLNSWDVFTNWL-NH2 735 845 Ac-LEANITASLEQAQIQQEKNMYELQKLNSWDVFTNWL-NH2 736 845 Ac-LEANITASLEQAQIQQEKNMYELQKLNSWDVFTNWL-NH2 736 846 Ac-RAKFKQLLQHYREVAAAKSSENDRLRLLLKQMUPS-NH2 1526 847 Ac-Abu-DDE-Abu-MNSVKNGTYDYPKYEEESKLNRNEIKGVKL-NH2 1527 856 Ac-WQEWEQKVRYLEANISQSLEQAQIQQEKNMYELQKL-NH2 739 860 Ac-DEYDASISQVNEKINQSLAFIRKSDELLHNVNAGK-NH2 740 861 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWN-NH2 741 862 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASLW-NH2 742 863 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASL-NH2 743 864 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWAS-NH2 744 865 Ac-QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARILAVERYLKDQ-NH2 745 866 Ac-DREINNYTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 746 867 Ac-NNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDK-NH2 747 868 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWAAA-NH2 748 869 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWAAAANWF-NH2 749 870 Ac-YTSLIHSLIEESQNQQEKNEQELLELDAAASLWNWF-NH2 750 871 Ac-YTSLIHSLIEESQNQQEKNEQELLAAAKWASLWNWF-NH2 751 872 Ac-YTSLIHSLIEESQNQQEKNEQAAAELDKWASLWNWF-NH2 752 873 Ac-YTSLIHSLIEESQNQQEKAAAELLELDKWASLWNWF-NH2 753 874 Ac-YTSLIHSLIEESQNQAAANEQELLELDKWASLWNWF-NH2 754 875 Ac-YTSLIHSLIEESAAAQEKNEQELLELDKWASLWNWF-NH2 755 876 Ac-YTSLIHSLIAAAQNQQEKNEQELLELDKWASLWNWF-NH2 756 877 Ac-YTSLIHAAAEESQNQQEKNEQELLELDKWASLWNWF-NH2 757 878 Ac-YTSAAASLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 758 879 Ac-EIWNNMTWMEWDRENEKINQSLAFIRKSDELLHNV-NH2 759 880 Ac-YISEVNEEINQSLAFIRKADELLENVDKWASLWNWF-NH2 760 881 Ac-TSVITIELSNIKENKANGTDAKVKLIKQELDKYKN-NH2 761 882 YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWFMG-NH2 762 883 Ac-NEKINQSLAFIRKSDELLHNV-NH2 763 884 Biotin-YDPLVFPSDEFDASISQVNEKINQSLAFIRKSDFL-NH2 764 885 Biotin-PLVFPSDEFDASISQVNEKINQSLAFIRKSDELLH-NH2 765 886 Biotin-VFPSDEFDASISQVNEKINQSLAFIRKSDELLHNV-NH2 766 887 Biotin-DEFDASISQVNEKINQSLAFIRKSDELLHNVNAGK-NH2 767 888 Biotin-VYPSDEFDASISQVNEKINQSLAFIRKSDELLHNV-NH2 768 889 Biotin-VYPSDEYDASISQVNEEINQALAYIRKADELLENV-NH2 769 890 Ac-VYPSDEFDASISQVQEEIQQALAFIRKADELLEQV-NH2 770 891 Ac-NYTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 771 892 Ac-NNYTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 772 893 Ac-INNYTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 773 894 Ac-EINNYTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 774 895 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWFN-NH2 775 896 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWFNI-NH2 776 897 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWFNIT-NH2 777 898 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWFNITN-NH2 778 899 Ac-YDPLVFPSDEFDASISQVNEKINQSLAFIRKSDELLHNVNAGK-NH2 779 900 Ac-NYTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWFN-NH2 780 901 Ac-NNYTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWFNI-NH2 781 905 Ac-KCRAKFKQLLQHYREVAAAKSSENDRLRLLLKQMCPSLDVDSIIPRTPD-NH2 782 906 Ac-RAKFKQLLQHYREVAAAKSSENDRLRLLLKQMCPSLDVDSIIPRTPD-NH2 783 907 Ac-VYPSDEYDASISQVNEEINQALAYIAAADELLENV-NH2 784 909 Ac-YDASISQVNEEINQALAYIRKADELL-NH2 785 910 Ac-M-Nle-WMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL-NH2 1528 911 Ac-KNGTYDYPKYEEESKLNRNEIKGVKLSSMGVYQI-NH2 787 912 Ac-VTEKIQMASDNINDLIQSGVNTRLLTIQSHVQNYI-NH2 788 913 QNQQEKNEQELLELDKWASLWNWF-NH2 789 914 Ac-QNQQEKNEQELLELDKWASLWNWF-NH2 790 915 LWNWF-NH2 791 916 ELLELDKWASLWNWF-NH2 792 917 EKNEQELLELDKWASLWNWF-NH2 793 918 SLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 794 919 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNW 795 920 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWN 796 921 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASLW 797 922 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASL 798 923 TSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 799 924 SLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 800 925 LIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 801 926 IHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 802 940 Ac-AAVALLPAVLLALLAPSELEIKRYKNRVASRKCRAKFKQLLQHYREVAAAK-NH2 803 941 Ac-AAVALLPAVLLALLAPCRAKFKQLLQHYREVAAAKSSENDRLRLLLKQMCP-NH2 804 942 Ac-YTSLIHSLIEESQNQQEKNNNIERDWEMWTMNNWIQ-NH2 805 944 VYPSDEYDASISQVNEEINQALAYIRKADELLENV-NH2 806 945 Ac-LMQLARQLMQLARQMKQLADSLMQLARQVSRLESA-NH2 807 946 Ac-WMEWDREINNYTSLIHSLIEESQNQQEKNEQELL-NH2 808 947 Ac-MEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL-NH2 809 948 Ac-EWDREINNYTSLIHSLIEESQNQQEKNEQELLEL-NH2 810 949 Ac-MEWDREINNYTSLIHSLIEESQNQQEKNEQELLE-NH2 811 950 Biotin-W-Nle-EWDREINNYTSLIHSLIEESQNQQEKNEQELLEL-NH2 1529 951 Ac-YLEYDREINNYTSLIHSLIEESQNQQEKNEQELLEL-NH2 813 952 Ac-IKQFINMWQEVGKAMYA-NH2 814 953 Ac-IRKSDELL-NH2 815 954 Decanoyl-IRKSDELL-NH2 815 955 Acetyl-Aca-Aca-IRKSDELL-NH2 1530 956 Ac-YDASISQV-NH2 816 957 Ac-NEKINQSL-NH2 817 958 Ac-SISQVNEEINQALAYIRKADELL-NH2 818 959 Ac-QVNEEINQALAYIRKADELL-NH2 819 960 Ac-EEINQALAYIRKADELL-NH 820 961 Ac-NQALAYIRKADELL-NH2 821 962 Ac-LAYIRKADELL-NH2 822 963 FDASISQVNEKINQALAFIRKSDELL-NH2 823 964 Ac-W-Nle-EWDREINNYTSLIHSLIEESQNQQEKNEQELLEL-NH2 1531 965 Ac-ASRKCRAKFKQLLQHYREVAAAKSSENDRLRLLLKQMCPSLDVDS-NH2 825 967 Ac-WLEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL-NH2 827 968 Ac-YVKGEPIINFYDPLVFPSDEFDASISQVNEKINQSL-NH2 828 969 Ac-VYPSDEYDASISQVNEEINQSLAYIRKADELLHNV-NH2 829 970 Ac-YDASISQVNEEINQALAYIRKADELLENV-NH2 830 971 Ac-YDASISQVNEEINQALAYIRKADELLE-NH2 831 972 Ac-VYPSDEYDASISQVNEEINQALAYIRKAAELLHNV-NH2 832 973 Ac-VYPSDEYDASISQVNEEINQALAYIRKALELLHNV-NH2 833 974 Decanoyl-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 834 975 Ac-VYPSDEYDASISQVNEEINQLLAYIRKLDELLENV-NH2 835 976 Ac-DEYDASISQVNEKINQSLAFIRKSDELL-NH2 836 977 Ac-SNDQGSGYAADKESTQKAFDGIThKVNSVIEKTNT-NH2 837 978 Ac-ESTQKAFDGITNKVNSVIEKTNTQFEAVGKEFGNLEKR-NH2 838 979 Ac-DGITNKVNSVIEKTNTQFEAVGKEFGNLEKRLENLNK-NH2 839 980 Ac-DSNVKNLYDKVRSQLRDNVKELGNGAFEFYHK-NH2 840 981 Ac-RDNVKELGNGAFEFYHKADDEALNSVKNGTYDYPKY-NH2 841 982 Ac-EFYHKADDEALNSVKNGTYDYPKY-NH2 842 983 Ac-AAVALLPAVLLALLAPAADKESTQKAFDGITNKVNS-NH2 843 984 Ac-AAVALLPAVLLALLAPAADSNVKNLYDKVRSQLRDN-NH2 844 985 Ac-KESTQKAFDGITNKVNSV-NH2 845 986 Ac-IEKTNTQFEAVGKEFGNLER-NH2 846 987 Ac-RLENLNKRVEDGFLDVWTYNAELLVALENE-NH2 847 988 Ac-SNVKNLYDKVRSQLRDN-NH2 848 989 Ac-WMEWDREINNYTSLIHSLIEESQNQQEKNEQEL-NH2 849 990 Ac-WMEWDREINNYTSLIHSLIEESQNQQEKNEQE-NH2 850 991 Ac-MEWDREINNYTSLIHSLIEESQNQQEKNEQEL-NH2 851 992 Ac-MEWDREINNYTSLIHSLIEESQNQQEKNEQE-NH2 852 993 Ac-EWDREINNYTSLIHSLIEESQNQQEKNEQELLE-NH2 853 994 Ac-EWDREINNYTSLIHSLIEESQNQQEKNEQELL-NH2 854 995 Ac-EWDREINNYTSLIHSLIEESQNQQEKNEQEL-NH2 855 996 Ac-YTKFIYTLLEESQNQQEKNEQELLELDKWASLWNWF-NH2 856 997 Ac-YMKQLADSLMQLARQVSRLESA-NH2 857 998 Ac-YLMQLARQMKQLADSLMQLARQVSRLESA-NH2 858 999 Ac-YQEWERKVDFLEENITALLEEAQIQQEKNMYELQKL-NH2 859 1000 Ac-WMAWAAAINNYTSLIHSLIEESQNQQEKNEQEEEEE-NH2 860 1001 Ac-YASLIAALIEESQNQQEKNEQELLELAKWAALWAWF-NH2 861 1002 [Ac-EWDREINNYTSLIHSLIEESQNQQEKNEQEGGC-NH2]dimer 862 1003 Ac-YDISIELNKAKSDLEESKEWIKKSNQKLDSIGNWH-NH2 863 1004 Biotinyl-IDISIELNKAKSDLEESKEWIKKSNQKLDSIGNWH-NH2 548 1005 Ac-YTSLI-OH 865 1006 Fmoc-HSLIEE-OH 866 1007 Fmoc-SQNQQEK-OH 867 1008 Fmoc-NEQELLEL-OH 868 1009 Fmoc-DKWASL-OH 869 1010 Fmoc-WNWF-OH 870 1011 Ac-AKTLERTWDTLNHLLFISSALYKLNLKSVAQITLSI-NH2 871 1012 Ac-NITLQAKIKQFINMWQEVGKAMYA-NH2 872 1013 Ac-LENERTLDFHDSNVKNLYDKVRLQLRDN-NH2 873 1014 Ac-LENERTLDFHDSNVKNLYDKVRLQLRDNVKELGNG-NH2 874 1015 Ac-TLDFHDSNVKNLYDKVRLQLRDNVKELGNGAFEF-NH2 875 1016 Ac-IDISIELNKAKSDLEESKEWIKKSNQKLDSIGNWH-NH2 548 1021 Biotinyl-SISQVNEEINQALAYIRKADELL-NH2 877 1022 Biotinyl-SISQVNEEINQSLAYIRKSDELL-NH2 878 1023 Ac-SISQVNEEINQSLAYIRKSDELL-NH2 879 1024 Ac-IDISIELNKAKSDLEESKEWIEKSNQELDSIGNWE-NH2 39 1025 Ac-IDISIELNKAKSDLEESKEWIKKSNQELDSIGNWH-NH2 864 1026 Ac-IDISIELNKAKSDLEEAKEWIKKANQKLDSIGNWH-NH2 79 1027 Ac-IDISIELNKAKSDLEESKEWIKKANQKLDSIGNWH-NH2 80 1028 Ac-IDISIELNKAKSDLEEAKEWIKKSNQKLDSIGNWH-NH2 548 1029 Biotinyl-NSVALDPIDISIELNKAKSDLEESKEWIKKSNQKL-NH2 880 1030 Biotinyl-ALDPIDISIELNKAKSDLEESKEWIKKSNQKLDSI-NH2 881 1031 desAminoTyrosine-NSVALDPIDISIELNKAKSDLEESKEWIKKSNQKL-NH2 882 1032 desAminoTyrosine-ALDPIDISIELNKAKSDLEESKEWIKKSNQKLDSI-NH2 883 1033 Ac-YDASISQVNEEINQALAFIRKADEL-NH2 1533 1034 Ac-YDASISQVNEEINQSLAYIRKADELL-NH2 1534 1035 Biotinyl-YDASISQVNEEINQALAYIRKADELL-NH2 890 1036 Biotinyl-YDASISQVNEEINQSLAFIRKSDELL-NH2 885 1037 Ac-YDASISQVNEEINQSLAFIRKSDELL-NH2 885 1038 Ac-WLEWDREINNYTSLIHSLIEESQNQQEKNEQEL-NH2 887 1039 Biotinyl-IDISIELNKAKSDLEESKEWIRRSNQKLDSIGNWH-NH2 888 1044 Ac-YESTQKAFDGITNKVNSVIEKTNTQFEAVGKEFGNLEKR-NH2 81 1045 Biotin-DEYDASISQVNEKINQSLAFIRKSDELL-NH2 82 1046 Ac-MEWDREINNYTSLIHSLIEESQNQQEKNEQELL-NH2 571 1047 Ac-WQEWEQKVRYLEANISQSLEQAQIQQEKNMYEL-NH2 892 1048 Ac-WQEWEQKVRYLEANISQSLEQAQIQQEKNEYEL-NH2 893 1049 Ac-WQEWEQKVRYLEANITALLEQAQIQQEKNEYEL-NH2 894 1050 Ac-WQEWEQKVRYLEANITALLEQAQIQQEKNMYEL-NH2 895 1051 Ac-WQEWEQKVRYLEANISQSLEQAQIQQEKNEYELQKL-NH2 896 1052 Ac-WQEWEQKVRYLEANITALLEQAQIQQEKNEYELQKL-NH2 897 1053 Ac-WQEWEQKVRYLEANITALLEQAQIQQEKNMYELQKL-NH2 898 1054 Ac-IDISIELNKAKSDLEESKEWIEKSNQKLDSIGNWH-NH2 1535 1055 Ac-EFGNLEKRLENLNKRVEDGFLDVWTYNAELLVALENE-NH2 899 1056 Ac-EDGFLDVWTYNAELLVLMENERTLDFHDSNVKNLYDKVRMQL-NH2 900 1057 Ac-SISQVNEKINQSLAFIRKSDELL-NH2 901 1058 desaminoTyr-SISQVNEKINQSLAFIRKSDELL-NH2 902 1059 Ac-SISQVNEKINQSLAYIRKSDELL-NH2 903 1060 Ac-QQLLDVVKRQQEMLRLTVWGTKNLQARVTAIEKYLKDQ-NH2 904 1061 YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWFC 905 1062 Ac-FDASISQVNEKINQSLAYIRKSDELL-NH2 906 1063 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWA 907 1064 Indole-3-acetyl-DEFDASISQVNEKINQSLAFIRKSDELL-NH2 908 1065 Indole-3-acetyl-DEFDESISQVNEKINQSLAFIRKSDELL-NH2 909 1066 Indole-3-acetyl-DEFDESISQVNEKIEQSLAFIRKSDELL-NH2 910 1067 Indole-3-acetyl-DEFDESISQVNEKIEESLAFIRKSDELL-NH2 911 1068 Indole-3-acetyl-DEFDESISQVNEKIEESLQFIRKSDELL-NH2 912 1069 Indole-3-acetyl-GGGGGDEFDASISQVNEKINQSLAFIRKSDELL-NH2 913 1070 2-Napthoyl-DEFDASISQVNEKINQSLAFIRKSDELL-NH2 914 1071 desNH2Tyr-DEFDASISQVNEKINQSLAFIRKSDELL-NH2 915 1072 biotin-ALDPIDISIELNKAKSDLEESKEWIRRSNQKLDSI-NH2 916 1073 Ac-YDASISQVNEKINQALAYIRKADELLHNVNAGKST-NH2 917 1074 Ac-VYFSDEYDASISQVNEKINQALAYIRKADELLHNV-NH2 918 1075 Ac-VYPSDEYDASISQVNEKINQSLAYIRKSDELLHNV-NH2 1536 1076 Ac-WGWGYGYG-NH2 919 1077 Ac-YGWGWGWGF-NH2 920 1078 Ac-WQEWEQKVRYLEANITALQEQAQIQAEKAEYELQKL-NH2 921 1079 Ac-WQEWEQKVRYLEAEITALQEEAQIQAEKAEYELQKL-NH2 922 1081 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWAS 923 1082 Ac-VWPSDEFDASISQVNEKINQSLAFIRKSDELLHNV-NH2 924 1083 Ac-SKNISEQIDQIKKDEQKEGTGWGLGGKWWTSDWGV-NH2 925 1084 Ac-LSKNISEQIDQIKKDEQKEGTGWGLGGKWWTSDWG-NH2 926 1085 Ac-DLSKNISEQIDQIKKDEQKEGTGWGLGGKWWTSDW-NH2 927 1086 Ac-EDLSKNISEQIDQIKKDEQKEGTGWGLGGKWWTSD-NH2 928 1087 Ac-IEDLSKNISEQIDQIKKDEQKEGTGWGLGGKWWTS-NH2 929 1088 Ac-GIEDLSKNISEQIDQIKKDEQKEGTGWGLGGKWWT-NH2 930 1089 Ac-IGIEDLSKNISEQIDQIKKDEQKEGTGWGLGGKWW-NH2 931 1090 2-Napthoyl--PSDEFDASISQVNEKINQSLAFIRKSDELLFHNVN-NH2 932 1091 Ac-VYPSDEYDASISQVNEKINQALAYIRKADELLENV-NH2 933 1092 Ac-VYPSDEFDASISQVNEKINQALAFIRKADELLENV-NH2 934 1093 Ac-VYPSDEYDASISQVNEKINQALAYIREADELLENV-NH2 935 1094 Biotinyl-YDASISQVNEKINQSLAFIRESDELL-NH2 936 1095 Ac-AIGIEDLSKNISEQIDQIKKDEQKEGTGWGLGGKW-NH2 937 1096 Ac-AAIGIEDLSKNISEQIDQIKKDEQKEGTGWGLGGK-NH2 938 1097 Ac-DAAIGIEDLSKNISEQIDQIKKDEQKEGTGWGLGG-NH2 939 1098 Ac-PDAAIGIEDLSKNISEQIDQIKKDEQKEGTGWGLG-NH2 940 1099 Ac-NITDKIDQIIHDFVDKTLPDQGDNDNWWTGWRQWI-NH2 941 1100 Ac-KNITDKIDQIIHDFVDKTLPDQGDNDNWWTGWRQW-NH2 942 1101 Ac-TKNITDKIDQIIHDFVDKTLPDQGDNDNWWTGWRQ-NH2 943 1102 Ac-WTKNITDKIDQIIHDFVDKTLPDQGDNDNWWTGWR-NH2 944 1103 Ac-DWTKNITDKIDQIIHDFVDKTLPDQGDNDNWWTGW-NH2 945 1104 Ac-HDWTKNITDKIDQIIHDFVDKTLPDQGDNDNWWTG-NH2 946 1105 Ac-PHDWTKNITDKIDQIIHDFVDKTLPDQGDNDNWWT-NH2 947 1106 Ac-EPHDWTKNITDKIDQIIHDFVDKTLPDQGDNDNWW-NH2 948 1107 Ac-IEPHDWTKNITDKIDQIIHDFVDKTLPDQGDNDNW-NH2 949 1108 Ac-AIEPHDWTKNITDKIDQIIHDFVDKTLPDQGDNDN-NH2 950 1109 Ac-AAIEPHDWTKNITDKIDQIIHDFVDKTLPDQGDND-NH2 951 1110 Ac-DAAIEPHDWTKNITDKIDQIIHDFVDKTLPDQGDN-NH2 952 1111 Ac-LSPTVWLSVIWMMWYWGPSLYSILSPFLPLLPIFF-NH2 953 1112 Ac-GLSPTVWLSVIWMMWYWGPSLYSILSPFLPLLPIF-NH2 1345 1113 Ac-VGLSPTVWLSVIWMMWYWGPSLYSILSPFLPLLPI-NH2 1346 1114 Ac-FVGLSPTWLSVIWMMWYWGPSLYSILSPFLPLLP-NH2 1347 1115 Ac-WFVGLSPTVWLSVIWMMWYWGPSLYSILSPFLPLL-NH2 1348 1116 Ac-QWFVFLSPTVWLSVIWMMWYWGPSLYSILSPFLPL-NH2 1537 1117 Ac-VQWFVGLSPTVWLSVIWMMWYWGPSLYSILSPFLP-NH2 1350 1118 Ac-FVQWFVGLSPTVWLSVIWMMWYWGPSLYSILSPFL-NH2 1351 1119 Ac-PFVQWFVGLSPTVWLSVIWMMWYWGPSLYSILSPF-NH2 1352 1120 Ac-VPFVQWFVGLSPTVWLSVIWMMWYWGPSLYSILSP-NH2 1353 1121 Ac-LVPFVQWFVGLSPTVWLSVIWMMWYWGPSLYSILS-NH2 1354 1122 H-NHTTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKW-OH 954 1123 H-QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARILAVERYLKDQ-OH 955 1124 Ac-VYPSDEFDASISQVNEKINQSLAFIREADELLENV-NH2 956 1125 Ac-VFPSDEFDASISQVNEKINQSLAYIREADELLENV-NH2 957 1126 Ac-DEFDASISQVNEKINQSLAYIREADELL-NH2 958 1127 Ac-NEQELLELDKWASLWNWFGGGGDEFDASISQVNEKINQSLAFIRKSDELL-NH2 959 1128 Ac-LELDKWASLWNWFGGGGDEFDASISQVNEKINQSLAFIRKSDELL-NH2 960 1129 Naphthoyl-EGEGEGEGDEFDASISQVNEKINQSLAFIRKSDELL-NH2 961 1130 Ac-ASRKCRAKFKQLLQHYREVAAAKSSENDRLRLLLKQMCPSLDV-NH2 962 1131 Naphthoyl-GDEEDASISQVNEKINQSLAFIRKSDELL-NH2 963 1132 Naphthoyl-GDEEDASESQVNEKINQSLAFIRKSDELL-NH2 964 1133 Naphthoyl-GDEEDASESQQNEKINQSLAFIRKSDELL-NH2 965 1134 Naphthoyl-GDEEDASESQQNEKQNQSLAFIRKSDELL-NH2 966 1135 Naphthoyl-GDEEDASESQQNEKQNQSEAFIRKSDELL-NH2 967 1136 Ac-WGDEFDESISQVNEKIEESLAFIRKSDELL-NH2 968 1137 Ac-YTSLGGDEFDESISQVNEKIEESLAFIRKSDELLGGWNWF-NH2 969 1138 Ac-YTSLIHSLGGDEFDESISQVNEKIEESLAFIRKSDELLGGWASLWNWF-NH 970 1139 2-Naphthoyl-GDEFDESISQVNEKIEESLAFIRKSDELL-NH2 971 1140 2-Naphthoyl-GDEEDESISQVNEKIEESLAFIRKSDELL-NH2 972 1141 2-Naphthoyl-GDEEDESISQVQEKIEESLAFIRKSDELL-NH2 973 1142 2-Naphthoyl-GDEEDESISQVQEKIEESLLFIRKSDELL-NH2 974 1143 Biotin-GDEYDESISQVNEKIEESLAFIRKSDELL-NH2 975 1144 2-Naphthoyl-GDEYDESISQVNEKIEESLAFIRKSDELL-NH2 976 1145 Ac-YTSLIHSLIDEQEKIEELAFIRKSDELLELDKWNWF-NH2 977 1146 VYPSDEYDASISQVNEEINQALAYIRKADELLENV-NH2 978 1147 Ac-NNLLRAIEAQQHLLQLTVWGSKQLQARILAVERYLKDQ-NH2 979 1148 GGGVYPSDEYDASISQVNEEINQALAYIRKADELLENV-NH2 980 1149 Ac-NNLLRAIEAQQHLLQLTVWGEKQLQARILAVERYLKDQ-NH2 981 1150 Ac-PTRVNYILIIGVLVLAbuEVTGVRADVHLL-NH2 1538 1151 Ac-PTRVNYILIIGVLVLAbuEVTGVRADVHLLEQPGNLW-NH2 1539 1152 Ac-PEKTPLLPTRVNYILIIGVLVLAbuEVTGVRADVHLL-NH2 1540 1153 AhaGGGVYPSDEYDASISQVNEEINQALAYIRKADELLENV-NH2 1541 1155 Ac-YTSLIHSLGGDEFDESISQVNEKIEESLAFIRKSDELL-NH2 986 1156 Ac-YTSLGGDEFDESISQVNEKIEESLAFIRKSDELL-NH2 987 1157 Ac-DEFDESISQVNEKIEESLAFIRKSDELLGGWASLWNWF-NH2 988 1158 Ac-DEFDESISQVNEKIEESLAFIRKSDELLGGWNWF-NH2 989 1159 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKASLWNWF-NH2 990 1160 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKSLWN WF-NH2 991 1161 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKLWNWF-NH2 992 1162 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWNWF-NH2 993 1163 Ac-MTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKASLWNWF-NH2 994 1164 Ac-MTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKSLWNWF-NH2 995 1165 Ac-MTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKLWNWF-NH2 996 1166 Ac-MTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWNWF-NH2 997 1167 Ac-MTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWASLWN-NH2 998 1168 Ac-MTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWASL-NH2 999 1169 (Pyr)HWSY(2-napthyl-D-Ala)LRPG-NH2 1542 1170 Ac-WNWFDEFDESISQVNEKIEESLAFIRKSDELLWNWF-NH2 1001 1171 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKYASLYNYF-NH2 1002 1172 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKYAYLYNYF-NH2 1003 1173 2-Naphthoyl-AcaAcaAcaDEFDESISQVNEKIEESLAFIRKSDELLAcaAcaAcaW-NH2 1543 1174 2-Naphthoyl-AcaAcaAcaGDEFDESISQVNEKIEESLAFIRKSDELLAcaAcaAcaW-NH2 1544 1175 2-Naphthoyl-GDEFDESISQVNEKIEESLAFIRESDELL-NH2 1006 1176 2-Naphthoyl-GDEFDESISQVNEKIEESLAFIEESDELL-NH2 1007 1177 Ac-WQEWEQKVNYLEANITALLEQAQIQQEKNEYELQKL-NH2 1008 1178 Ac-WQEWEQKVDYLEANITALLEQAQIQQEKNEYELQKL-NH2 1009 1179 Ac-WQEWEQKVRWLEANITALLEQAQIQQEKNEYELQKL-NH2 1010 1180 Ac-WQEWEKQVRYLEANITALLEQAQIQQEKNEYELQKL-NH2 1011 1181 Ac-WQEWEHQVRYLEANITALLEQAQIQQEKNEYELQKL-NH2 1012 1182 Ac-WQEWEHKVRYLEANITALLEQAQIQQEKNEYELQKL-NH2 1013 1183 Ac-WQEWDREVRYLEANITALLEQAQIQQEKNEYELQKL-NH2 1014 1184 Ac-WQEWEREVRYLEANITALLEQAQIQQEKNEYELQKL-NH2 1015 1185 Ac-WQEWERQVRYLEANITALLEQAQIQQEKNEYELQKL-NH2 1016 1186 Ac-WQEWEQKVKYLEANITALLEQAQIQQEKNEYELQKL-NH2 1017 1187 Ac-WQEWEQKVRFLEANITALLEQAQIQQEKNEYELQKL-NH2 1018 1188 Ac-VNalPSDEYDASISQVNEEINQALAYIRKADELLENV-NH2 1545 1189 Ac-VNalPSDENalDASISQVNEEINQALAYIRKADELLENV-NH2 1546 1190 Ac-VNalPSDEYDASISQVNEEINQALANalIRKADELLENV-NH2 1547 1191 Ac-VYPSDEFDASISQVNEKINQSLAFIREADELLFNFF-NH2 1022 1192 Ac-VYPSDEYDASISQVNEEINQALAYIRKADELLFNFF-NH2 1023 1193 Ac-YTSLITALLEQAQIQQEKNEYELQKLDKWASLWNWF-NH2 1024 1194 Ac-YTSLITALLEQAQIQQEKNEYELQKLDKWASLWEWF-NH2 1548 1195 Ac-YTSLITALLEQAQIQQEKNEYELQKLDEWASLWEWF-NH2 1026 1196 Ac-YTSLITALLEQAQIQQEKNEYELQELDEWASLWEWF-NH2 1027 1197 Ac-YTSLITALLEEAQIQQEKNEYELQELDEWASLWEWF-NH2 1028 1198 Naphthoyl-Aua-Aua-Aua-TALLEQAQIQQEKNEYELQKLAua-Aua-Aua-W-NH2 1549 1199 Ac-WAAWEQKVRYLEANITALLEQAQIQQEKNEYELQKL-NH2 1030 1200 Ac-WQEAAQKVRYLEANITALLEQAQIQQEKNEYELQKL-NH2 1031 1201 Ac-WQEWAAKVRYLEANITALLEQAQIQQEKNEYELQKL-NH2 1032 1202 Ac-WQAAEQKVRYLEANITALLEQAQIQQEKNEYELQKL-NH2 1550 1203 Ac-WQEWEAAVRYLEANITALLEQAQIQQEKNEYELQKL-NH2 1551 1204 Ac-WQEWEQAARYLEANITALLEQAQIQQEKNEYELQKL-NH2 1552 1205 Ac-WQEWEQKAAYLEANITALLEQAQIQQEKNEYELQKL-NH2 1553 1206 Ac-WQEWEQKVAALEANITALLEQAQIQQEKNEYELQKL-NH2 1554 1207 Ac-WQEWEQKVRYLEANITALLEQAQIQQEKNEYELQKLGGGGWASLWNF-NH2 1555 1208 2-Naphthoyl-GDEFDASISQVNEKINQSLAFIRKSDELT-NH2 1039 1209 2-Naphthoyl-GDEFDASISQVNEKINQSLAFTRKSDELT-NH2 1040 1210 2-Naphthoyl-GDEFDASISQVNEKTNQSLAFTRKSDELT-NH2 1037 1211 2-Naphthoyl-GDEFDASISQTNEKTNQSLAFTRKSDELT-NH2 1038 1212 2-Naphthoyl-GDEFDASTSQTNEKTNQSLAFTRKSDELT-NH2 1039 1213 2-Naphthoyl-GDEYDASTSQTNEKTNQSLAFTRKSDELT-NH2 1040 1214 2-Naphthoyl-GDEFDEEISQVNEKIEESLAFIRKSDELL-NH2 1041 1215 2-Naphthoyl-GDEFDASISQVNEKINQSLAFIRKSDELA-NH2 1042 1216 2-Naphthoyl-GDEFDASASQANEKANQSLAFARKSDELA-NH2 1043 1217 2-Naphthoyl-GDEFDESISQVNEKIEESLAFTRKSDELL-NH2 1044 1218 2-Naphthoyl-GDEFDESISQVNEKTEESLAFIRKSDELL-NH2 1045 1219 2-Naphthoyl-GDEFDESISQTNEKIEESLAFIRKSDELL-NH2 1046 1220 2-Naphthoyl-GDEFDESTSQVNEKIEESLAFIRKSDELL-NH2 1047 1221 Ac-WNWFDEFDESTSQVNEKIEESLAFIRKSDELLWNWF-NH2 1048 1222 Ac-WNWFDEFDESTSQTNEKIEESLAFIRKSDELLWNWF-NH2 1049 1223 Ac-WNWFDEFDESTSQTNEKTEESLAFIRKSDELLWNWF-NH2 1050 1224 Ac-LQAGFFLLTRILTIPQSLDSWWTSLNFLGGTTVAL-NH2 1355 1225 Ac-YThLIYTLLEESQNQQEKNEQELLELDKWASLWSWF-NH2 1051 1226 Ac-WQEWEQKVRYLEANITALLEQAQIQQEKNEYELQKLDKWASLWNWF-NH2 1052 1227 Ac-NNMTWQEWEQKVRYLEANITALLEQAQIQQEKNEYELQKLDKWASLWNWF-NH2 1053 1230 Ac-WNWFIEESDELLWNWF-NH2 1054 1231 2-Naphthoyl-GFIEESDELLW-NH2 1055 1232 Ac-WFIEESDELLW-NH2 1056 1233 2-Naphthoyl-GFNFFIEESDELLFNFF-NH2 1057 1234 2-Naphthoyl-GESDELW-NH2 1058 1235 Ac-WNWFGDEFDESISQVQEEIEESLAFIEESDELLGGWNWF-NH2 1059 1236 Ac-WNWFIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 1356 1237 Ac-YTSLITALLEQAQIQQEENEYELQALDEWASLWEWF-NH2 1025 1238 Ac-YTSLIHSLGGDEFDESISQVNEEIEESLAFIEESDELLGGWASLWNWF-NH2 1060 1239 2-Naphthoyl-GDEFDESISQVQEEIEESLAFIEESDELL-NH2 1061 1240 H-QARQLLSSIMQQQNNLLRAIEAQQHLLQLTVWGIKQLQARILAVERYLKDQ-OH 1062 1241 Ac-CPKYVKQNTLKLATGMRNVPEKQTR-NH2 1063 1242 Ac-GLFGAIAGFIENGWEGMIDGWYGFRHQNSC-NH2 1064 1243 Ac-LNFLGGT-NH2 1065 1244 Ac-LDSWWTSLNFLGGT-NH2 1066 1245 Ac-ILTIPQSLDSWWTSLNFLGGT-NH2 1067 1246 Ac-GFFLLTRILTIPQSLDSWWTSLNFLGGT-NH2 1068 1247 Ac-WQEWEQKITALLEQAQIQQEKNEYELQKLDKWASLWNWF-NH2 1069 1248 Ac-WNWFITALLEQAQIQQEKNEYELQKLDKWASLWNWF-NH2 1070 1249 Ac-WQEWEQKITALLEQAQIQQEKNEYELQKLDKWASLWEWF-NH2 1071 1250 Ac-WQEWEQKVRYLEANITALLEQAQIQQEKIEYELQKL-NH2 1072 1251 Ac-WQEWEQKVRYLEAQITALLEQAQIQQEKIEYELQKL-NH2 1073 1252 Ac-KENKANGTDAKVKLIKQELDKYKNAVTELQLLMQS-NH2 1074 1253 Ac-NIKENKANGTDAKVKLIKQELDKYKNAVTELQLLM-NH2 1075 1254 (FS)-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 1076 1255 2-Naphthoyl-GWNWFAcaDEFDESISQVQEEIEESLAFIEESDELLAcaWNWF-NH2 1556 1256 Ac-WNWFGDEFDESISQVNEKIEESLAFIEESDELLGWNWF-NH2 1078 1257 Ac-WNWFGDEFDESISQVNEKIEESLAFIRKSDELLGWNWF-NH2 1079 1258 Ac-WNWF-Aca-DEFDESISQVNEKIEESLAFIRKSDELL-Aca-WNWF-NH2 1557 1259 Ac-WNWF-Aca-DEFDESISQVNEKIEESLAFIEESDELL-Aca-WNWF-NH2 1558 1260 Ac-EESQNQQEKNEQELLELDKWA-NH2 1082 1261 EESQNQQEKNEQELLELDKWA 1083 1262 Ac-CGTTDRSGAPTYSWGANDTDVFVLNNTRPPLGNWFG-NH2 1084 1263 Ac-GVEHRLEAACNWTRGERADLEDRDRSELSP-NH2 1085 1264 Ac-CVREGNASRAWVAVTPTVATRDGKLPT-NH2 1086 1265 Ac-CFSPRHHWTTQDANASIYPG-NH2 1087 1266 Ac-LQHYREVAAAKSSENDRLRLLLKQMCPSLDVDS-NH2 1088 1267 Ac-WQEWDREISNYTSLITALLEQAQIQQEKNEYELQKLDEWASLWEWF-NH2 1089 1268 Ac-CWQEWDREISNYTSLITALLEQAQIQQEKNEYELQKLDEWASLWEWFC-NH2 1090 1269 Ac-WQEWDREISNYTSLITALLEQAQIQQEKNEYELQKLDEWEWF-NH2 1091 1270 Ac-CWQEWDREISNYTSLITALLEQAQIQQEKNEYELQKLDEWEWFC-NH2 1092 1271 Ac-GQNSQSPTSNHSPTSAPPTAPGYRWA-NH2 1093 1272 Ac-PGSSTTSTGPARTALTTAQGTSLYPSA-NH2 1094 1273 Ac-PGSSTTSTGPARTALTTAQGTSLYPSAAATKPSDGNATA-NH2 1095 1275 Ac-WQEWDREITALLEQAQIQQEKNEYELQKLDKWASLWNWF-NH2 1097 1276 Ac-WQEWDREITALLEQAQIQQEKNEYELQKLDEWASLWEWF-NH2 1098 1277 Ac-WQEWDREITALLEQAQIQQEKNEYELQKLDEWEWF-NH2 1099 1278 Ac-WQEWEREITALLEQAQIQQEKNEYELQKLDEWEWF-NH2 1100 1279 Ac-WQEWEREITALLEQAQIQQEKNEYELQKLIEWEWF-NH2 1101 1280 Ac-WQEWEREITALLEQAQIQQEKIEYELQKLDEWEWF-NH2 1102 1281 Ac-WQEWEITALLEQAQIQQEKNEYELQKLDEWEWF-NH2 1103 1282 Ac-WQEWEITALLEQAQIQQEKNEYELQKLIEWEWF-NH2 1104 1283 Ac-WQEWEITALLEQAQIQQEKIEYELQKLDEWEWF-NH2 1105 1284 Ac-WQEWEITALLEQAQIQQEKIEYELQKLIEWEWF-NH2 1106 1285 Ac-WQEWDREIDEYDASISQVNEKINQALAYIREADELWEWF-NH2 1107 1286 Ac-WQEWEREIDEYDASISQVNEKINQALAYIREADELWEWF-NH2 1108 1287 Ac-WQEWEIDEYDASISQVNEKINQALAYIREADELWEWF-NH2 1109 1288 Ac-WQEWDREIDEYDASISQVNEEINQALAYIREADELWEWF-NH2 1110 1289 Ac-WQEWEREIDEYDASISQVNEEINQALAYIREADELWEWF-NH2 1111 1290 Ac-WQEWEIDEYDASISQVNEEINQALAYIREADELWEWF-NH2 1112 1291 Ac-WQEWDEYDASISQVNEKINQALAYIREADELWEWF-NH2 1113 1292 Ac-WQEWDEYDASISQVNEEINQALAYIREADELWEWF-NH2 1114 1293 Ac-WQEWEQKITALLEQAQIQQEKIEYELQKLIEWEWF-NH2 1115 1294 Ac-WQEWEQKITALLEQAQIQQEKIEYELQKLIEWASLWEWF-NH2 1116 1295 Ac-WQEWEITALLEQAQIQQEKIEYELQKLIEWASLWEWF-NH2 1117 1298 -VYFSDEYDASISQVNEEINQALAYIRKADELLENV-NH2 1160 1299 Ac-WVYPSDEYDASISQVNEEINQALAYIRKADELLENVWNWF-NH2 1120 1300 YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 1121 1301 Ac-WQEWDEYDASISQVNEKINQALAYIREADELWAWF-NH2 1122 1302 Ac-WQAWDEYDASISQVNEKINQALAYIREADELWAWF-NH2 1123 1303 Ac-WQAWDEYDASISQVNEKINQALAYIREADELWEWF-NH2 1124 1304 Biotin-YDPLVFPSDEFDASISQVNEKINQSLAFIRKSDEL-NH2 1125 1305 Biotin-YDPLVFPSDEFDASISQVNEKINQSLAF-NH2 1126 1306 Biotin-QVNEKINQSLAFIRKSDELLHNVNAGKST-NH2 1127 1307 Ac-WMEWDREI-NH2 1128 1308 Ac-WQEWEQKI-NH2 1129 1309 Ac-WQEWEQKITALLEQAQIQQEKIEYELQKLIKWASLWEWF-NH2 1130 1310 Ac-WQEWEQKITALLEQAQIQQEKIEYELQKLIEWASLWEWF-NH2 1131 1311 Ac-WQEWEREISAYTSLITALLEQAQIQQEKIEYELQKLIEWEWF-NH2 1132 1312 Ac-WQEWEREISAYTSLITALLEQAQIQQEKIEYELQKEWEWF-NH2 1133 1313 Ac-WQEWEREISAYTSLITALLEQAQIQQEKIEYELQKEWEW-NH2 1134 1314 Ac-WQEWEREISAYTSLITALLEQAQIQQEKIEYELQKLIEWEW-NH2 1135 1315 Ac-FNLSDHSESIQKKFQLMKKHVNKIGVDSDPIGSWLW-NH2 1136 1316 Ac-DHSESIQKKFQLMKKHVNKIGVDSDPIGSWLRGIF-NH2 1137 1317 Ac-WSVKQANLTTSLLGDLLDDVTSIRHAVLQNRA-NH2 1138 1318 Biotin-WMEWDREI-NH2 1128 1319 Biotin-NNMTWMEWDREINNYTSL-NH2 1139 1320 Ac-GAASLTLTVQARQLLSGIVQQQNNLLRAIEAQQHLL-NH2 1140 1321 Ac-ASLTLTVQARQLLSGIVQQQNNLLRAIEAQQHLLQL-NH2 1141 1322 Ac-VSVGNTLYYVNKQEGKSLYVKGEPIINFYDPLVF-NH2 1142 1323 Ac-QHWSYGLRPG-NH2 1143 1324 Ac-WQEWEQKIQHWSYGLRPGWASLWEWF-NH2 1144 1325 Ac-WQEWEQKIQHWSYGLRPGWEWF-NH2 1145 1326 Ac-WNWFQHWSYGLRPGWNWF-NH2 1146 1327 Ac-FNFFQHWSYGLRPGFNFF-NH2 1147 1328 Ac-GAGAQHWSYGLRPGAGAG-NH2 1148 1329 PLLVLQAGFFLLTRILTIPQSLDSWWTSLNFLGGT 482 1330 Ac-WQEWEQKITALLEQAQIQQEKIEYELQKLAKWASLWEWF-NH2 1149 1331 Ac-WQEWEQKITALLEQAQIQQEKIEYELQKLAEWASLWEWF-NH2 1150 1332 Ac-WQEWEQKITALLEQAQIQQEKAEYELQKLAEWASLWEWF-NH2 1151 1333 Ac-WQEWEQKITALLEQAQIQQEKAEYELQKLAEWASLWAWF-NH2 1152 1334 Ac-WQEWEQKITALLEQAQIQQEKAEYELQKLAKWASLWAWF-NH2 1153 1335 Ac-TNKAVVSLSNGVSVLTSKVLDLKNYIDKQLLPIVNK-NH2 1154 1336 Ac-KAVVSLSNGVSVLTSKVLDLKNYIDKQLLPIVNKQS-NH2 1155 1337 Ac-WQEWEQKITALLEQAQIQQEKNEYELQKLIEWEWF-NH2 1156 1338 Ac-WQEWEQKITALLEQAQIQQEKGEYELQKLIEWEWF-NH2 1157 1339 Ac-WQEWEQKITALLEQAQIQQEKIEYELQKLDKWEWF-NH2 1158 1340 Ac-YDPLVFPSDEFDASISQVNEKINQSLAF-NH2 1159 1341 Fluor--VYPSDEYDASISQVNEEINQALAYIRKADELLENV-NH2 1160 1342 Fluor-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 1161 1344 Ac-SGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL-NH2 1162 1345 Ac-QQQNNLLRAIEAQQHLLQLTVWGIKQLQARILAVERYLKDQ-NH2 1163 1346 Ac-SGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARILAVERYLKDQ-NH2 1164 1347 Ac-WQEWEQKITALLEQAQIQQEKNEYELQKLAEWASLWAWF-NH2 1165 1348 Ac-WQEWEQKITALLEQAQIQQEKNEYELQKLAEWASLWAW-NH2 1166 1349 Ac-WQEWEQKITALLEQAQIQQEKAEYELQKLAEWASLWAW-NH2 1167 4350 Ac-WQEWEQKITALLEQAQIQQEKNEYELQKLAEWAGLWAWF-NH2 1168 1351 Ac-WQEWEQKITALLEQAQIQQEKNEYELQKLAEWAGLWAW-NH2 1169 1352 Ac-WQEWEQKITALLEQAQIQQEKAEYELQKLAEWAGLWAW-NH2 1170 1353 Ac-WQEWEQKITALLEQAQIQQEKNEYELQKLDKWAGLWEWF-NH2 1171 1354 Ac-WQEWQHWSYGLRPGWEWF-NH2 1172 1355 Ac-WQAWQHWSYGLRPGWAWF-NH2 1173 1356 Biotinyl-WQEWEQKITALLEQAQIQQEKNEYELQKLDKWASLWEWF-NH2 1174 1357 WQEWEQKITALLEQAQIQQEKNEYELQKLDKWASLWEWF 1175 1358 WQEWEQKITALLEQAQIQQEKIEYELQKLIEWEWF 1176 1361 Ac-AGSTMGARSMTLTVQARQLLSGIVQQQNNLLRAIEAQQ-NH2 1179 1362 Ac-AGSAMGAASLTLSAQSRTLLAGIVQQQQQLLDVVKRQQ-NH2 1180 1363 Ac-AGSAMGAASTALTAQSRTLLAGIVQQQQQLLDVVKRQQ-NH2 1181 1364 Ac-ALTAQSRTLLAGIVQQQQQLLDVVKRQQELLRLTVWGT-NH2 1182 1365 Ac-TLSAQSRTLLAGIVQQQQQLLDVVKRQQEMLRLTVWGT-NH2 1183 1366 Ac-TLTVQARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGI-NH2 1184 1367 Ac-WQAWIEYEAELSQVKEKIEQSLAYIREADELWAWF-NH2 1185 1368 Ac-WQAWIEYEASLSQAKEKIEESKAYIREADELWAWF-NH2 1186 1369 Ac-WQAWIEYERLLVQAKLKIAIAKLYIAKELLEWAWF-NH2 1187 1370 Ac-WQAWIEYERLLVQVKLKIAIALLYIAKELLEWAWF-NH2 1188 1371 Ac-WQAWIELERLLVQVKLKLAIAKLEIAKELLEWAWF-NH2 1189 1372 Ac-GEWTYDDATKTFTVTEGGH-NH2 1190 1373 Ac-WQEWEQKIGEWTYDDATKTFTVTEGGHWASLWEWF-NH2 1191 1374 Ac-GEWTYDDATKTFTVTE-NH2 1192 1375 Ac-WQEWEQKIGEWTYDDATKTFTVTEWASLWEWF-NH2 1193 1376 Ac-MHRFDYRT-NH2 1194 1377 Ac-WQEWEQKIMHRFDYRTWASLWEWF-NH2 1195 1378 Ac-MHRFNWSTGGG-NH2 1196 1379 Ac-WQEWEQKIMHRFNWSTGGGWASLWEWF-NH2 1197 1380 Ac-MHRFNWST-NH2 1198 1381 Ac-WQEWEQKIMHRFNWSTWASLWEWF-NH2 1199 1382 Ac-LLVPLARIMTMSSVHGGG-NH2 1200 1383 Ac-WQEWEQKlLLVPLARIMTMSSVHGGGWASLWEWF-NH2 1201 1384 Ac-LLVPLARIMTMSSVH-NH2 1202 1385 Ac-WQEWEQKILLVPLARIMTMSSVHWASLWEWF-NH2 1203 1386 TALLEQAQIQQEKNEYELQKLDK 1204 1387 Ac-TALLEQAQIQQEKNEYELQKLDK-NH2 1205 1388 Ac-TALLEQAQIQQEKIEYELQKLIE-NH2 1206 1389 TALLEQAQIQQEKIEYELQKLIE 1207 1390 Ac-QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARILAVERY-NH2 1208 1391 Rhod-QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARILAVERY-NH2 1209 1392 Ac-GAASLTLSAQSRTLLAGIVQQQQQLLDVVKRQQEML-NH2 1210 1393 Ac-GSAMGAASLTLSAQSRTLLAGIVQQQQQLLDVVKRQQEML-NH2 1211 1394 Ac-PALSTGLIHLHQNIVDVQFLFGVGSSIASWAIKWEY-NH2 1212 1395 Ac-PALSTGLIHLHQNIVDVQFLYGVGSSIASWAIK-NH2 1213 1396 Ac-LSTTQWQVLPUSFTTLPALSTGLIHLHQNIVDVQY-NH2 1561 1397 Ac-FRKFPEATFSRUGSGPRITPRUMVDFPFRLWHY-NH2 1562 1398 Ac-DFPFRLWHFPUTINYTIFKVRLFVGGVEHRLEAAUNWTR-NH2♂ 1563 1399 Ac-YVGGVEHRLEAAUNWTRGERUDLEDRDRSELSPL-NH2 1564 1400 MVYPSDEYDASISQVNEEINQALAYIRKADELLENV 1218 1402 Ac-GPLLVLQAGFFLLTRILTIPQSLDSWWTSLNFLGG-NH2 1220 1403 Ac-LGPLLVLQAGFFLLTRILTIPQSLDSWWTSLNFLG-NH2 1221 1404 Ac-FLGPLLVLQAGFFLLTRILTIPQSLDSWWTSLNFL-NH2 1222 1405 Ac-YTNTIYTLLEESQNQQEKNEQELLELDKWASLWNWF-NH2 1357 1406 YTNTIYTLLEESQNQQEKNEQELLELDKWASLWNWF 1357 1407 Ac-YTGIIYNLLEESQNQQEKNEQELLELDKWANLWNWF-NH2 1358 1408 YTGIIYNLLEESQNQQEKNEQELLELDKWANLWNWF 1359 1409 Ac-YTSLIYSLLEKSQIQQEKNEQELLELDKWASLWNWF-NH2 1360 1410 YTSLIYSLLEKSQIQQEKNEQELLELDKWASLWNWF 1360 1411 Ac-EKSQIQQEKNEQELLELDKWA-NH2 1362 1412 EKSQIQQEKNEQELLELDKWA 1362 1413 Ac-EQAQIQQEKNEYELQKLDKWA-NH2 1364 1414 Ac-YTSLIGSLIEESQIQQERNEQELLELDRWASLWEWF-NH2 1223 1415 Ac-YTXLIHSLIXESQNQQXKNEQELXELDKWASLWNWF-NH2 1366 1416 Ac-YTXLIHSLIWESQNQQXKNEQELXELD-NH2 1565 1417 Ac-YTSLIHSLIEESQNQQEKNEQELLELD-NH2 1368 1418 Ac-WQEQEXKITALLXQAQIQQXKNEYELXKLDKWASLWEWF-NH2 1566 1419 Ac-XKITALLXQAQIQQXKNEYELXKLDKWASLWEWF-NH2 1370 1420 Ac-WQEWWXKITALLXQAQIQQXKNEYELXKLD-NH2 1567 1421 Ac-WEQKITALLEQAQIQQEKNEYELQKLD-NH2 1372 1422 Ac-WEXKITALLXQAQIQQXKNEYELXKLD-NH2 1568 1423 Ac-XKITALLXQAQIQQXKNEYELXKLD-NH2 1374 1425 Ac-QKITALLEQAQIQQEKNEYELQKLD-NH2 1375 1426 Ac-QKITALLEQAQIQQEKNEYELQKLDKWASLWEWF-NH2 1381 1427 Ac-WQEWEQKITALLEQAQIQQEKNEYELQKLD-NH2 1379 1428 Ac-VYPSDEYDASISQVNEEINQALAYIRKADELLEN-OH 1237 1429 Ac-VYPSDEYDASISQVNEEINQALAYIRKADELLE-OH 1237 1430 Ac-VYPSDEYDASISQVNEEINQALAYIRKADELL-OH 1376 1431 Ac-VYPSDEYDASISQVNEEINQALAYIRKADEL-OH 1378 1432 YPSDEYDASISQVNEEINQALAYIRKADELLENV-NH2 1227 1433 PSDEYDASISQVNEEINQALAYIRKADELLENV-NH2 1228 1434 SDEYDASISQVNEEINQALAYIRKADELLENV-NH2 1229 1435 DEYDASISQVNEEINQALAYIRKADELLENV-NH2 1230 1436 Ac-VYPSDEYDASISQVDEEINQALAYIRKADELLENV-NH2 1231 1437 Ac-VYPSDEYDASISQVNEEIDQALAYIRKADELLENV-NH2 1232 1438 Ac-VYPSDEYDASISQVNEEINQALAYIRKADELLEDV-NH2 1233 1439 Ac-VYPSDEYDASISQVDEEIDQALAYIRKADELLENV-NH2 1234 1440 Ac-LLSTNKAVVSLSNGVSVLTSKVLDLKNYIDKQLLP-NH2 1235 1441 Ac-LSTNKAVVSLSNGVSVLTSKVLDLKNYIDKQLLPI-NH2 1236 1442 Ac-STNKAVVSLSNGVSVLTSKVLDLKNYIDKQLLPIV-NH2 1382 1443 Ac-TNKAVVSLSNGVSVLTSKVLDLKNYIDKQLLPIVN-NH2 1383 1444 Ac-NKAVVSLSNGVSVLTSKVLDLKNYIDKQLLPIVNK-NH2 1384 1445 Ac-KAVVSLSNGVSVLTSKVLDLKNYIDKQLLPIVNKQ-NH2 1385 1446 Ac-AVVSLSNGVSVLTSKVLDLKNYIDKQLLPIVNKQS-NH2 1155 1447 Ac-VVSLSNGVSVLTSKVDLKNYIDKQWLLPIVNKQSU-NH2 1570 1448 Ac-VSLSNGVSVLTSKVLDLKNYIDKQLLPIVNKQSUS-NH2 1571 1449 Ac-SLSNGVSVLTSKVLDLKNYIDKQLLPIVNKQSUSI-NH2 1572 1450 Ac-LSNGVSVLTSKVLDLKNYIDKQLLPIVNKQSUSIS-NH2 1573 1451 Ac-SNGVSVLTSKVLDLKNYIDKQLLPIVNKQSUSISN-NH2 1574 1452 Ac-NGVSVLTSKVLDLKNYIDKQLLPIVNKQSUSISNI-NH2 1575 1453 Ac-GVSVLTSKVLDLKNYIDKQLLPIVNKQSUSISNIE-NH2 1576 1454 Ac-VSVLTSKVLDLKNYIDKQLLPIVNKQSUSISINIET-NH2 1577 1455 Ac-SVLTSKVLDLKNYIDKQLLPIVNKQSUSISNIETV-NH2 1578 1456 Ac-VLTSKVLDLKNYIDKQLLPIVNKQSUSISNIETVI-NH2 1579 1457 Ac-LTSKVLDLKNYIDKQLLPIVNKQSUSISNIETVIE-NH2 1580 1458 Ac-TSKVLDLKNYIDKQLLPIVNKQSUSISNIETVIEF-NH2 1581 1459 Ac-SKVLDLKNYIDKQLLPIVNKQSUSISNIETVIEFQ-NH2 1582 1460 Ac-KVLDLKNYIDKQLLPIVNKQSUSISNIETVIEFQQ-NH2 1583 1461 Ac-VLDLKNYIDKQLLPIVNKQSUSISNIETVIEFQQK-NH2 1584 1462 Ac-LDLKNYIDKQLLPIVNKQSUSISNIETVIEFQQKN-NH2 1585 1463 Ac-DLKNYIDKQLLPIVNKQSUSISNIETVIEFQQKNN-NH2 1586 1464 Ac-LKNYIDKQLLPIVNKQSUSISNIETVIEFQQKNNR-NH2 1587 1465 Ac-KNYIDKQLLPIVNKQSUSISNIETVIEFQQKNNRL-NH2 1588 1466 Ac-NYIDKQLLPIVNKQSUSISNIETVIEFQQKNNRLL-NH2 1589 1467 Ac-YIDKQLLPIVNKQSUSISNIETVIEFQQKNNRLLE-NH2 1590 1468 Ac-IDKQLLPIVNKQSUSISNIETVIEFQQKNNRLLEI-NH2 1591 1469 Ac-DKQLLPIVNKQSUSISNIETVIEFQQKNNRLLEIT-NH2 1592 1470 Ac-KQLLPIVNKQSUSISNIETVIEFQQKNNRLLEITR-NH2 1593 1471 Ac-QLLPIVNKQSUSISNIETVIEFQQKNNRLLEITRE-NH2 1594 1472 Ac-VYPSDEYDASISQVNEEINQALA 1412 1473 QVNEEINQALAYIRKADELLENV-NH2 1413 1474 VYPSDEYDASISQVNEEINQALAYIRKADELLENV 1414 1475 Ac-DEYDASISQVNEEINQALAYIREADEL-NH2 1415 1476 Ac-DEYDASISQVNEKINQALAYIREADEL-NH2 1416 1477 Ac-DDECLNSVKNGTYDFPKFEEESKLNRNEIKGVKLS-NH2 1417 1478 Ac-DDE-Abu-LNSVKNGTYDFPKFEEESKLNRNEIKGVKLS-NH2 1595 1479 Ac-YHKCDDECLNSVKNGTFDFPKFEEESKLNRNEIKGVKLSS-NH2 1596 1480 Ac-YHK-Abu-DDE-Abu-LNSVKNGTFDFPKFEEESKLNRNEIKGVKLSS-NH2 1597 1481 Ac-YTSLIHSLIEESQIQQEKNEQELLELDKWASLWNWF-NH2 1598 1482 Ac-YTSLIHSLIEESQNQQEKNEYELLELDKWASLWNWF-NH2 1599 1483 Ac-YTSLIHSLIEESQIQQEKNEYELLELDKWASLWNWF-NH2 1600 1484 Ac-YTSLIHSLIEESQIQQEKNEYELQKLDKWASLWNWF-NH2 1244 1485 Ac-YTSLIHSLIEESQNQQEKNEQELQKLDKWASLWNWF-NH2 1245 1486 Ac-YTSLIHSLIEESQNQQEKNEYELQKLDKWASLWNWF-NH2 1421 1487 Ac-YTSLIHSLIEESQIQQEKNEQELQKLDKWASLWNWF-NH2 1422 1488 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWEWF-NH2 1423 1489 Ac-YTSLIHSLIEESQIQQEKNEQELLELDKWASLWEWF-NH2 1424 1490 Ac-YTSLIHSLIEESQNQQEKNEYELLELDKWASLWEWF-NH2 1425 1491 Ac-YTSLIHSLIEESQIQQEKNEYELLELDKWASLWEWF-NH2 1426 1492 Ac-YTSLIHSLIEESQIQQEKNEYELQKLDKWASLWEWF-NH2 1601 1493 Ac-YTSLIHSLIEESQNQQEKNEQELQKLDKWASLWEWF-NH2 1428 1494 Ac-YTSLIHSLIEESQNQQEKNEYELQKLDKWASLWEWF-NH2 1429 1495 Ac-YTSLIHSLIEESQIQQEKNEQELQKLDKWASLWEWF-NH2 1430 1496 Ac-WQEWEQKITALLEQAQIQQEKNEYELQKLDKEWWF-NH2 1602 1497 Ac-WQEWEQKITALLEQAQIQQEKNEYELQKLIEWASLWEWF-NH2 1432 1498 Ac-WQEWEQKITALLEQAQIQQEKNEYELQKLAKWASLWEWF-NH2 1256 1499 Ac-WQEWEQKITALLEQAQIQQEKNEYELQKLIKWASLWEWF-NH2 1257 1500 Ac-WQEWEQKITALLEQAQIQQEKNEYELQKLIEWAGLWEWF-NH2 1258 1501 Ac-WQEWEQKITALLEQAQIQQEKNEYELQKLAKWAGLWEWF-NH2 1260 1502 Ac-WQEWEQKITALLEQAQIQQEKNEYELQKLIKWAGLWEWF-NH2 1259 1503 Ac-WQEWEQKITALLEQAQIQQEKNEYELQKLIEWAGLWAWF-NH2 1261 1504 Ac-WQEWEQKITALLEQAQIQQEKNEYELQKLAKWAGLWAWF-NH2 1262 1505 Ac-WQEWEQKITALLEQAQIQQEKNEYELQKLIKWAGLWAWF-NH2 1263 1506 Ac-WQEWEQKITALLEQAQIQQEKGEYELQKLDKQEQF-NH2 1267 1507 Ac-WQEWEQKITALLEQAQIQQEKGEYELLELDKWEWF-NH2 1265 1508 Ac-WQEWEQKITALLEQAQIQQEKGEYELQKLAKWEWF-NH2 1266 1509 Ac-WQEWEQKITALLEQAQIQQEKGEYELQKLDWQWEF-NH2 1603 1510 Ac-WQEWEQKITALLEQAQIQQEKGEYELLELAKWEWF-NH2 1268 1511 Ac-WEQWEQKITALLEQAQIQQEKNEYELLELDKWEWF-NH2 1604 1512 Ac-WQEWEQKITALLEQAQIQQEKNEYELEEELIEWASLWEWF-NH2 1605 1513 Ac-WQEWEQKITALLEQAQIQQEKNEYELLELIEWAGLWEWF-NH2 1271 1514 Ac-WQEWEQKITALLEQAQIQQEKNEYELLELIEWAGLWAWF-NH2 1272 1515 Ac-WQEWEREITALLEQAQIQQEKNEYELQKLIEWASLWEWF-NH2 1273 1516 Ac-WQEWEREIQQEKNEYELQKLDKWASLWEWF-NH2 1274 1517 Ac-WQEWEREIQQEKGEYELQKLIEWEWF-NH2 1275 1518 Ac-WQEWQAQIQQEKNEYELQKLDKWASLWEWF-NH2 1606 1519 Ac-WQEWQAQIQQEKGEYELQKLIEWEWF-NH2 1277

It is to be understood that such core polypeptide sequences, per se, can exhibit antiviral and/or anti-fusogenic activity and are considered part of the present invention. Among the core polypeptide sequences are, for example, ones which have been derived from individual viral protein sequences. Also among the core polypeptide sequences are, for example, ones whose amino acid sequences are derived from greater than one viral protein sequence (e.g., an HIV-1, HIV-2 and SIV -derived core polypeptide).

The amino- and carboxy-termini of such core polypeptides (either per se or as part of a hybrid polypeptide) can be as discussed above for hybrid polypeptides. It is noted that while a number of the core polypeptides listed in Table 1, above, are depicted with modified, e.g., blocked amino and/or carboxy termini, that any core polypeptide comprising an unmodified primary amino acid sequence as depicted in Table 1 are to also be considered part of the present invention.

In addition, such core polypeptides can exhibit amino acid substitutions, deletions and/or insertions as discussed, above, for enhancer polypeptide sequences as long as the particular core polypeptide's antiviral and/or antifusogenic activity (either per se or as part of a hybrid polypeptide) is not abolished. With respect to amino acid deletions, it is preferable that the resulting core polypeptide is at least about 4-6 amino acid residues in length. With respect to amino acid insertions, preferable insertions are no greater than about 50 amino acid residues, and, more preferably no more than about 15 amino acid residues. It is also preferable that core polypeptide insertions be amino- and/or carboxy-terminal insertions.

Among such amino and/or carboxy-terminal insertions are ones which comprise amino acid sequences amino and/or carboxy to the endogenous protein sequence from which the core polypeptide is derived. For example, if the core polypeptide is derived from gp41 protein, such an insertion would comprise an amino and/or carboxy-terminal insertion comprising a gp41 amino acid sequence adjacent to the gp41 core polypeptide sequence.

The invention further relates to the association of the enhancer core polypeptide sequences to types of molecules other than peptides. For example, the enhancer peptide sequences may be linked to nucleic acid molecules (e.g., DNA or RNA) or any type of small organic molecule for the purpose of enhancing the pharmacokinetic properties of said molecules.

5.2. SYNTHESIS OF PEPTIDES

The enhancer, core and hybrid polypeptides of the invention may be synthesized or prepared by techniques well known in the art. See, for example, Creighton, 1983, Proteins: Structures and Molecular Principles, W. H. Freeman and Co., NY, which is incorporated herein by reference in its entirety. Hybrid polypeptides may be prepared using conventional step-wise solution or solid phase synthesis, fragment condensation, F-MOC or T-BOC chemistry. (see, e.g., Chemical Approaches to the Synthesis of Peptides and Proteins, Williams et al., Eds., 1997, CRC Press, Boca Raton Fla., and references cited therein; Solid Phase Peptide Synthesis: A Practical Approach, Atherton & Sheppard, Eds., 1989, IRL Press, Oxford, England, and references cited therein). Likewise the amino- and/or carboxy-terminal modifications.

The enhancer, core and hybrid polypeptides of the invention can be purified by art-known techniques such as normal and reverse phase high performance liquid chromatography, ion exchange chromatography, gel electrophoresis, affinity chromatography, size exclusion, precipitation and the like. The actual conditions used to purify a particular polypeptide will depend, in part, on synthesis strategy and on factors such as net charge, hydrophobicity, hydrophilicity, solubility, stability etc., and will be apparent to those having skill in the art.

Hybrid, enhancer and core polypeptides may also be made using recombinant DNA techniques. Here, the nucleotide sequences encoding the polypeptides of the invention may be synthesized, and/or cloned, and expressed according to techniques well known to those of ordinary skill in the art. See, for example, Sambrook, et al., 1989, Molecular Cloning, A Laboratory Manual, Vols. 1-3, Cold Spring Harbor Press, NY.

One may obtain the DNA segment encoding the polypeptide of interest using a variety of molecular biological techniques, generally known to those skilled in the art. For example, polymerase chain reaction (PCR) may be used to generate the DNA fragment encoding the protein of interest. Alternatively, the DNA fragment may be obtained from a commercial source.

The DNA encoding the polypeptides of interest may be recombinantly engineered into a variety of host vector systems that also provide for replication of the DNA in large scale. These vectors can be designed to contain the necessary elements for directing the transcription and/or translation of the DNA sequence encoding the hybrid polypeptide.

Vectors that may be used include, but are not limited to, those derived from recombinant bacteriophage DNA, plasmid DNA or cosmid DNA. For example, plasmid vectors such as pcDNA3, pBR322, pUC 19/18, pUC 118, 119 and the M13 mp series of vectors may be used. Bacteriophage vectors may include λgt10, λgt11, λgt18-23, λZAP/R and the EMBL series of bacteriophage vectors. Cosmid vectors that may be utilized include, but are not limited to, pJB8, pCV 103, pCV 107, pCV 108, pTM, PMCS, pNNL, pHSG274, COS202, COS203, pWE15, pWE16 and the charomid 9 series of vectors.

Alternatively, recombinant virus vectors including, but not limited to, those derived from viruses such as herpes virus, retroviruses, vaccinia viruses, adenoviruses, adeno-associated viruses or bovine papilloma viruses plant viruses, such as tobacco mosaic virus and baculovirus may be engineered.

In order to express a biologically active polypeptide, the nucleotide sequence coding for the protein may be inserted into an appropriate expression vector, i.e., a vector which contains the necessary elements for the transcription and translation of the inserted coding sequences. Methods which are well known to those skilled in the art can be used to construct expression vectors having the hybrid polypeptide coding sequence operatively associated with appropriate transcriptional/translational control signals. These methods include in vitro recombinant DNA techniques and synthetic techniques. See, for example, the techniques described in Sambrook, et al., 1992, Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory, N.Y. and Ausubel et al., 1989, Current Protocols in Molecular Biology, Greene Publishing Associates & Wiley Interscience, N.Y., each of which are incorporated herein by reference in its entirety.

The nucleic acid molecule encoding the hybrid, enhancer and core polypeptides of interest may be operatively associated with a variety of different promoter/enhancer elements. The promoter/enhancer elements may be selected to optimize for the expression of therapeutic amounts of protein. The expression elements of these vectors may vary in their strength and specificities. Depending on the host/vector system utilized, any one of a number of suitable transcription and translation elements may be used. The promoter may be in the form of the promoter which is naturally associated with the gene of interest. Alternatively, the DNA may be positioned under the control of a recombinant or heterologous promoter, i.e., a promoter that is not normally associated with that gene. For example, tissue specific promoter/enhancer elements may be used to regulate the expression of the transferred DNA in specific cell types.

Examples of transcriptional control regions that exhibit tissue specificity which have been described and could be used include, but are not limited to, elastase I gene control region which is active in pancreatic acinar cells (Swift et al., 1984, Cell 38:639-646; Ornitz et al., 1986, Cold Spring Harbor Symp. Ouant. Biol. 50:399-409; MacDonald, 1987, Hepatology 7:42S-51S); insulin gene control region which is active in pancreatic beta cells (Hanahan, 1985, Nature 315:115-122); immunoglobulin gene control region which is active in lymphoid cells (Grosschedl et al., 1984, Cell 38:647-658; Adams et al., 1985, Nature 318:533-538; Alexander et al., 1987, Mol. Cell. Biol. 7:1436-1444): albumin gene control region which is active in liver (Pinkert et al., 1987, Genes and Devel. 1:268-276) alpha-fetoprotein gene control region which is active in liver (Krumlauf et al., 1985, Mol. Cell. Biol. 5:1639-1648; Hammer et al., 1987, Science 235:53-58); alpha-1-antitrypsin gene control region which is active in liver (Kelsey et al., 1987, Genes and Devel. 1:161-171); beta-globin gene control region which is active in myeloid cells (Magram et al., 1985, Nature 315:338-340; Kollias et al., 1986, Cell 46:89-94); myelin basic protein gene control region which is active in oligodendrocyte cells in the brain (Readhead et al., 1987, Cell 48:703-712); myosin light chain-2 gene control region which is active in skeletal muscle (Shani, 1985, Nature 314:283-286); and gonadotropic releasing hormone gene control region which is active in the hypothalamus (Mason et al., 1986, Science 234:1372-1378). Promoters isolated from the genome of viruses that grow in mammalian cells, (e.g., vaccinia virus 7.5K, SV40, HSV, adenoviruses MLP, MMTV, LTR and CMV promoters) may be used, as well as promoters produced by recombinant DNA or synthetic techniques.

In some instances, the promoter elements may be constitutive or inducible promoters and can be used under the appropriate conditions to direct high level or regulated expression of the nucleotide sequence of interest. Expression of genes under the control of constitutive promoters does not require the presence of a specific substrate to induce gene expression and will occur under all conditions of cell growth. In contrast, expression of genes controlled by inducible promoters is responsive to the presence or absence of an inducing agent.

Specific initiation signals are also required for sufficient translation of inserted protein coding sequences. These signals include the ATG initiation codon and adjacent sequences. In cases where the entire coding sequence, including the initiation codon and adjacent sequences are inserted into the appropriate expression vectors, no additional translational control signals may be needed. However, in cases where only a portion of the coding sequence is inserted, exogenous translational control signals, including the ATG initiation codon must be provided. Furthermore, the initiation codon must be in phase with the reading frame of the protein coding sequences to ensure translation of the entire insert. These exogenous translational control signals and initiation codons can be of a variety of origins, both natural and synthetic. The efficiency of expression may be enhanced by the inclusion of transcription attenuation sequences, enhancer elements, etc.

5.3. PHARMACEUTICAL FORMULATIONS, DOSAGES AND MODES OF ADMINISTRATION

The peptides of the invention may be administered using techniques well known to those in the art. Preferably, agents are formulated and administered systemically. Techniques for formulation and administration may be found in “Remington's Pharmaceutical Sciences”, 18th ed., 1990, Mack Publishing Co., Easton, Pa. Suitable routes may include oral, rectal, vaginal, lung, transdermal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as, intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections, just to name a few. For intravenous injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer to name a few. In addition, infusion pumps may be used to deliver the peptides of the invention. For such transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

In instances wherein intracellular administration of the peptides of the invention or other inhibitory agents is preferred, techniques well known to those of ordinary skill in the art may be utilized. For example, such agents may be encapsulated into liposomes, or microspheres then administered as described above. Liposomes are spherical lipid bilayers with aqueous interiors. All molecules present in an aqueous solution at the time of liposome formation are incorporated into the aqueous interior. The liposomal contents are both protected from the external microenvironment and, because liposomes fuse with cell membranes, are effectively delivered into the cell cytoplasm. Additionally, due to their hydrophobicity, when small molecules are to be administered, direct intracellular administration may be achieved.

Nucleotide sequences encoding the peptides of the invention which are to be intracellularly administered may be expressed in cells of interest, using techniques well known to those of skill in the art. For example, expression vectors derived from viruses such as retroviruses, vaccinia viruses, adeno-associated viruses, herpes viruses, or bovine papilloma viruses, may be used for delivery and expression of such nucleotide sequences into the targeted cell population. Methods for the construction of such vectors and expression constructs are well known. See, for example, Sambrook et al., 1989, Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor NY, and Ausubel et al., 1989, Current Protocols in Molecular Biology, Greene Publishing Associates and Wiley Interscience, NY.

Effective dosages of the peptides of the invention to be administered may be determined through procedures well known to those in the art which address such parameters as biological half-life, bioavailability, and toxicity. In one embodiment, an effective hybrid polypeptide dosage range is from 0.1-100 μg/kg body weight. A therapeutically effective dose refers to that amount of the compound sufficient to result in amelioration of symptoms or a prolongation of survival in a patient. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD₅₀/ED₅₀. Compounds which exhibit large therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED₅₀ with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in the method of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC₅₀ (e.g., the concentration of the test compound which achieves a half-maximal inhibition of the fusogenic event, such as a half-maximal inhibition of viral infection relative to the amount of the event in the absence of the test compound) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography (HPLC) or any biological or immunological assay capable of measuring peptide levels.

The hybrid polypepties of the invention can also be administered in combination with at least one other therapeutic agent. Administration can be concomitantly or sequentially, including cycling therapy (that is, administration of a first compound for a period of time, followed by administration of a second antiviral compound for a period of time and repeating this sequential administration in order to reduce the development of resistance to one of the therapies).

In the case of viral infections, an effective amount of a hybrid polypeptide or a pharmaceutically acceptable derivative thereof can be administered in combination with at least one other antiviral agent. Such antiviral agents can include, but are not limited to DP-107, DP-178, cytokines, e.g., rIFN α, rIFN β, rIFN γ; inhibitors of reverse transcriptase, e.g., AZT, 3TC, D4T, ddI, and other dideoxynucleosidesor dideoxyfluoronucleosides; inhibitors of viral mRNA capping, such as ribavirin; inhibitors of HIV protease, such as ABT-538 and MK-639; amphotericin B as a lipid-binding molecule with anti-HIV activity; and castanospermine as an inhibitor of glycoprotein processing.

The hybrid and/or core polypeptides of the invention may, further, be utilized prophylactically for the prevention of disease. Hybrid and/or core polypeptides can act directly to prevent disease or, alternatively, can be used as vaccines, wherein the host raises antibodies against the hybrid polypeptides of the invention, which then serve to neutralize pathogenic organisms including, for example, inhibiting viral, bacterial and parasitic infection.

For all such treatments described above, the exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See e.g. Fingl et al., 1975, in “The Pharmacological Basis of Therapeutics”, Ch. 1 p1).

It should be noted that the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity, or to organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity). The magnitude of an administrated dose in the management of the oncogenic disorder of interest will vary with the severity of the condition to be treated and the route of administration. The dose and perhaps dose frequency, will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.

Use of pharmaceutically acceptable carriers to formulate the compounds herein disclosed for the practice of the invention into dosages suitable for systemic administration is within the scope of the invention. With proper choice of carrier and suitable manufacturing practice, the compositions of the present invention, in particular, those formulated as solutions, may be administered parenterally, such as by intravenous injection. The compounds can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration. Such carriers enable the compounds of the invention to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.

Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.

In addition to the active ingredients, these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. The preparations formulated for oral administration may be in the form of tablets, dragees, capsules, or solutions.

The pharmaceutical compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, spray drying, emulsifying, encapsulating, entrapping or lyophilizing processes.

Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, emulsions and suspensions of the active compounds may be prepared as appropriate oily injection mixtures. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, liposomes or other substances known in the art for making lipid or lipoptilic emulsions. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

Pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, trehalose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.

In instances where an enhancement of the host immune response is desired, the hybrid polypeptides may be formulated with a suitable adjuvant in order to enhance the immunological response. Such adjuvants may include, but are not limited to mineral gels such as aluminum hydroxide; surface active substances such as lysolecithin, pluronic polyols, polyanions; other peptides; oil emulsions; and potentially useful human adjuvants such as BCG and Corynebacterium parvum. Many methods may be used to introduce the vaccine formulations described here. These methods include but are not limited to oral, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, and intranasal routes.

6. EXAMPLE: IDENTIFICATION OF CONSENSUS AMINO ACID SEQUENCES THAT COMPRISE ENHANCER PEPTIDE SEQUENCES

The retroviral gp4l protein contains structural domains referred to as the α-helix region located in the C-terminal region of the protein and the leucine zipper region located in the N-terminal region of the protein. Alignment of the enhancer sequence regions contained within gp4l (FIGS. 2A and 2B) of gp41 from all currently published isolate sequences of HIV-1, HIV-2 and SIV identified the consensus amino acid sequences shown in FIG. 1.

As described in detail in the Examples presented below, such sequences represent enhancer peptide sequences in that linkage of these peptide sequences to a variety of different core polypeptides enhances the pharmacokinetic properties of the resultant hybrid polypeptides.

7. EXAMPLE: HYBRID POLYPEPTIDES THAT FUNCTION AS POTENT INHIBITORS OF HIV-1 INFECTION

T1249, as depicted in FIGS. 13A-D, is a hybrid polypeptide comprising enhancer peptide sequences linked to an HIV core polypeptide. As demonstrated below, the T1249 hybrid polypeptide exhibits enhanced pharmacokinetic properties and potent in vitro activity against HIV-1, HIV-2, and SIV isolates, with enhanced activity against HIV-1 clinical isolates in HuPBMC infectivity assays in vitro as well as in the HuPBMC SCID mouse model of HIV- 1 infection in vivo. In the biological assays described below, the activity of the T1249 is compared to the potent anti-viral T20 polypeptide. The T20 polypeptide, also known as DP-178, is derived from HIV-1 gp41 protein sequence, and is disclosed and claimed in U.S. Pat. No. 5,464,933.

7.1. MATERIALS AND METHODS 7.1.1. PEPTIDE SYNTHESIS AND PURIFICATION

Peptides were synthesized using Fast Moc chemistry. Generally, unless otherwise noted, the peptides contained amidated carboxyl termini and acetylated amino termini. Purification was carried out by reverse phase HPLC.

T1249 (Ac-WQEWEQKITALLEQAQIQQEKNEYELQKLDKWASLWEWF-NH2) (SEQ ID NO:1071) is a 39 amino acid peptide (MW=5036.7) composed entirely of naturally occurring amino acids and is blocked at the amino terminus by an acetyl group and the carboxyl terminus is blocked by an amido group to enhance stability. T1387 is a 23 amino acid peptide lacking enhancer peptide sequences (Ac-TALLEQAQIQQEKNEYELQKLDK-NH2) (SEQ ID NO:1205). Thus, T1387 represents the core polypeptide of the T1249 hybrid polypeptide. T1387 is blocked at its amino- and carboxy- termini in the same manner as T1 249.

In particular, T1249 was synthesized using standard solid-phase synthesis techniques. The identity of the principal peak in the HPLC trace was confirmed by mass spectroscopy to be T1249.

T1249 was readily purified by reverse phase chromatography on a 6-inch column packed with a C18, 10 micron, 120A support.

7.1.2. VIRUS

The HIV-1_(LA1) virus (Popovic, M. et al., 1984, Science 224:497-508) was propagated in CEM cells cultured in RPMI 1640 containing 10% fetal calf serum. Supernatant from the infected CEM cells was passed through a 0.2 μm filter and the infectious titer estimated in a microinfectivity assay using the AA5 cell line to support virus replication. For this purpose, 20 μl of serially diluted virus was added to 20 μl CEM cells at a concentration of 6×10⁵/ml in a 96-well microtitre plate. Each virus dilution was tested in triplicate. Cells were cultured for seven days by addition of fresh medium every other day. On day 7 post infection, supernatant samples were tested for virus replication as evidenced by reverse transcriptase activity released to the supernatant. The TCID₅₀ was calculated according to the Reed and Muench formula (Reed, L. J. et al., 1938, Am. J. Hyg. 27:493-497).

7.1.3. CELL FUSION ASSAY

Approximately 7×10⁴ Molt-4 cells were incubated with 1×10⁴ CEM cells chronically infected with the HIV-1_(LA1) virus in 96-well tissue culture plates in a final volume of 100 μl culture medium (RPM1 1640 containing 10% heat inactivated FBS, supplemented with 1% L-glutamine and 1% Pen-Strep) as previously described (Matthews, T. J. et al., 1987, Proc. Natl. Acad. Sci. USA 84: 5424-5428). Peptide inhibitors were added in a volume of 10 μl and the cell mixtures were incubated for 24 hr. at 37° C. in 5% CO₂. At that time, multinucleated giant cells (syncytia, five cell widths or larger) were counted by microscopic examination at 10× and 40× magnification which allowed visualization of the entire well in a single field. Treated cells were compared to infected, untreated controls and results expressed as percent inhibition of infected controls.

7.1.4. MAGI-CCR-5 INFECTIVITY ASSAYS

Approximately. 1×10⁶ Magi-CCR-5 cells (obtained through the NIH AIDS Research and Reference Reagent Program, Division of AIDS, NIAID; Chackerian, B. et al., 1997, J. Virol. 71: 3932-3939) were seeded into a 48-well tissue culture plate (approximately 2×10⁴ cells/well in a volume of 300 μl/well selective growth medium consisting of DMEM supplemented with 10% heat inactivated FBS, 1% L-glutamine, 1% Pen/Strep, Hygromycin B, Geneticin, and Puromycin) and allowed to attach overnight at 37° C., 5% CO₂. Cell confluency was approximately 30% by the following day. Seeding medium was removed and diluted peptide inhibitor added in volumes of 50 μl/well (media only in untreated controls), followed by 100 μl/well of diluted virus (desired input virus titre of 100-200 pfu/well). Finally, 250 μl of selective growth medium was added to each well and the plate incubated for 2 days at 37° C., 5% CO₂. Fixing and staining were done according to the protocol provided by NIAID with the MAGI-CCR5 cells. Briefly, medium was removed from the plate and 500 μl of fixative added to each well. Plates were allowed to fix for 5 minutes at room temp. Fixative was removed, each well washed twice with DPBS, and 200 μl of staining solution added to each well. The plate was then incubated at 37° C., 5% CO₂, for 50 minutes, staining solution removed, and each well washed twice with DPBS. The plate was allowed to air dry before blue cells were counted by microscopic, enumerating the entire well. Treated wells were compared to infected, untreated controls and results expressed as percent inhibition of infected controls.

7.1.5. REVERSE TRANSCRIPTASE ASSAY

The micro-reverse transcriptase (RT) assay was adapted from Goff et al. (Goff, S. et al., 1981, J. Virol. 38: 239-248) and Willey et al. (Willey, R. et al., 1988, J. Virol. 62: 139-147). Supernatants from virus/cell cultures were adjusted to 1% Triton-X100. 10 ul of each supernatant/Triton X-100 sample were added to 50 ul of RT cocktail (75 mM KC1, 2 mM Clevelands reagent, 5 mM MgCl₂, 5 μg/ml poly A, 0.25 units/ml oligo dT, 0.05% NP40, 50 mM Tris-HCl, pH 7.8, 0.5 μM non-radioactive dTTP, and 10 cci/ml ³²P-dTTP) in a 96-well U-bottom microtitre plate and incubated at 37° C. for 90 min. After incubation, 40 μl of reaction mixture from each well was transferred to a Schleicher and Schuell (S+S) dot blot apparatus, under partial vacuum, containing a gridded 96-well filter-mat (Wallac catalog #1450-423) and filter backing saturated with 2× SSC buffer (0.3M NaCl and 0.003M sodium citrate). Each well was washed 4 times with at least 200 μl 2× SSC using full vacuum. Minifold was disassembled and gridded filter paper removed and washed 3 times with 2× SSC. Finally, the filter membrane was drained on absorbent paper, allowed to air dry, and sealed in heat sealable bags. Samples were placed in a phosphorscreen cassette and an erased (at least 8 min) phosphorscreen applied and closed. Exposure was for 16 hr. Pixel Index Values (PIV), generated in volume reporting format retrieved from phosphorimaging (Molecular Dynamics Phosphorimager) blots, were used to determine the affected or inhibited fraction (Fa) for all doses of inhibitor(s) when compared to untreated, infected controls (analyzed by ImageQuant volume report, corrected for background).

7.1.6. HUMAN PBMC INFECTIVITY/NEUTRALIZATION ASSAY

The prototypic assay used cell lines where the primary isolate assay utilizes PBMC, obtained through Interstate Blood Bank, activated for 2-3 days with a combination of OKT3 (0.5 μg/ml) and CD28 antibodies (0.1 μg/ml). The target cells were banded on lymphocyte separation medium (LSM), washed, and frozen. Cells were thawed as required and activated as indicated above a minimum of 2-3 days prior to assay. In this 96-well format assay, cells were at a concentration of 2×10⁶/ml in 5% IL-2 medium and a final volume of 100 μl. Peptide stock solutions were made in DPBS (1 mg/ml). Peptide dilutions were performed in 20% FBS RPM1 1640/5% IL-2 complete medium.

7.1.7. IN VIVO HU-PBMC SCID MODEL OF HIV-1 INFECTION

Female SCID mice (5-7 weeks old) received 5-10×10⁷ adult human PBMC injected intraperitoneally. Two weeks after reconstitution, mice were infected IP on day 0 with 10³ TCID₅₀ HIV-1 9320 (AZT-sensitive isolate A018). Treatment with peptides was IP, bid, beginning day -1 and continuing through day 6. The extent of infection in blood cells, splenocytes, lymph nodes, and peritoneal cells was assayed by quantitative co-culture with human PBMC blasts weekly for three consecutive weeks following animal exanguinations and tissue harvest (day 7, approximately 12-18 hours following the last drug treatment). Co-culture supernatants were evaluated for HIV-1 p24 antigen production as a measure of virus infection (Immunotek Coulter kits and protocol).

7.1.8. RAT PHARMACOKINETIC STUDIES

250-300 g male CD rats, double jugular catheter, obtained from Charles River Laboratories were used. Peptides were injected in one jugular catheter in a volume of 200 μl of peptide solution (approximately 3.75 mg/ml), dosing solution concentration was determined using the Edelhoch method, (Edelhoch, 1967, Biochemistry 6:1948-1954) method and adjusted based on animal weight such that each animal received a dose of 2.5 mg/kg). Approximately 250-300 μl of blood was removed at predetermined time intervals (0, 15, 30 min and 1, 2, 4, 6, and 8 hours) and added to EDTA capiject tubes. Plasma was removed from pelleted cells upon centrifugation and either frozen or immediately processed for fluorescence HPLC analysis.

7.1.9. FLUORESCENCE HPLC ANALYSIS OF PLASMA SAMPLES

100 μl of sample plasma was added to 900 μl of precipitation buffer (acetonitrile, 0.1% TFA, detergent) resultingin precipitation of the majority of plasma proteins. Following centrifugation at 10,000 rpm for 10 min, 400 μl of the supernatant was removed and added to 600 μl of HPLC grade water. Serial dilutions were performed as dictated by concentration of peptide present in each sample in dilution buffer comprised of 40% precipitation buffer and 60% HPLC water. In addition to sample dilutions, serial dilutions of dosing solution were performed in buffer as well as in plasma and used to generate a standard curve relating peak area to known concentration of peptide. This curve was then used to calculate concentration of peptide in plasma taking into account all dilutions performed and quantity injected onto column.

7.1.10. XTT PROTOCOL

In order to measure cytotoxic/cytostatic effects of peptides, XTT assays (Weislow, O. S. et al., 1989, J. Natl. Cancer Inst. 81:577-586) were performed in the presence of varying concentrations of peptide in order to effectively establish a selective index (SI). A TC50 was determined in this assay by incubating cells in the presence and absence of serially diluted peptide followed by the addition of XTT. In surviving/metabolizing cells XTT is reduced to a soluble brown dye, XTT-formazan. Absorbance is read and comparisons made between readings in the presence and absence of peptide to determine a TC₅₀ utilizing the Karber method (see. e.g., Lennette, E. H. et al., eds., 1969, “Diagnostic Procedures for Viral and Rickettsial Infections,” American Public Health Association, Inc., fourth ed., pp. 47-52). Molt 4, CEM (80,000 cells/well) and a combination of the two cell types (70,000 and 10,000 respectively) were plated and incubated with serially diluted peptide for 24 hours in a total volume of 100 μl. Following incubation, 25 μl of XTT working stock (1 mg/ml XTT, 250 μM PMS in complete medium containing 5% DMSO) was added to each well and the plates incubated at 37° C. Color development was read and results used to express values generated from peptide containing wells as a percentage of the untreated control wells.

7.2. RESULTS 7.2.1. ANTIVIRAL ACTIVITY—FUSION ASSAYS

T1249 was directly compared to T20 in virus mediated cell—cell fusion assays conducted using chronically infected CEM cells mixed with uninfected Molt-4 cells, as shown in Table 2, below. T1249 fusion inhibition against lab isolates such as IIIb, MN, and RF is comparable to T20, and displays an approximately 2.5-5-fold improvement over T20. T1249 was also mor e active (3-28 fold improvement) than T20 against several syncytia-inducing clinical isolates, including an AZT resistant isolate (G691-2), a pre-AZT treatment isolate (G762-3), and 9320 (isolate used in HuPBMC-SCID studies). Most notably, T1249 was over 800-fold more potent than T20 against HIV-2 NIHZ.

TABLE 2 T20 T1249 Fold Virus Isolate (ng/ml) n (ng/ml) n Difference HIV-1 IIIb 2.5 9 1.0 9 2.5 HIV-1 G691-2 (AZT-R) 406.0 1 16.0 1 25 HIV-1 G762-3 (Pre-AZT) 340.1 1 12.2 1 28 HIV-1 MN 20.0 7 3.1 7 6 HIV-1 RF 6.1 7 2.1 7 3 HIV-1 9320 118.4 1 34.5 1 3 HIV-2 NIHZ 3610.0 >10 4.3 2 840

7.2.2. ANTIVIRAL ACTIVITY - Magi-CCR-5 INFECTIVITY ASSAYS

Magi-CCR-5 infectivity assays allow direct comparisons to be made of syncytia and non-syncytia inducing virus isolates, as well as comparisons between laboratory and clinical isolates. The assay is also a direct measure of virus infection (TAT expression following infection, transactivating an LTR driven beta-galactosidase production), as opposed to commonly used indirect measures of infectivity such as p24 antigen or reverse transcriptase production. Magi-CCR-5 infectivity assays (see Table 3 below) reveal that T1249 is consistently more effective than T20 against all isolates tested, in terms of both EC5 and Vn/Vo =0.1 inhibition calculations. T1249 shows considerable improvement in potency against the clinical isolate HIV-1 301714 (>25-fold), which is one of the least sensitive isolates to T20. In addition, T1249 is at least 100-fold more potent than T20 against the SIV isolate B670. These data, along with fusion data suggest that T1249 is a potent peptide inhibitor of HIV-1, HIV-2, and SIV.

TABLE 3 T20 T1249 EC-50 Vn/Vo = 0.1 Virus Vn/Vo = Vn/Vo = Fold Fold Isolate EC-50 0.1 EC-50 0.1 Difference Difference HIV-1 IIIB 42 80 8 10 5 8 9320 11 50 1 6 11 8 301714 1065 4000 43 105 25 38 (subtype B, NSI) G691-2 13 200 0.3 20 43 10 (AZT-R) pNL4-3 166 210 1 13 166 16 SIV-B670 2313 >10000 21 100 110 >100

7.2.3. ANTIVIRAL ACTIVITY—HUPBMC INFECTIVITY ASSAYS

T1249 was directly compared to T20 in HUPBMC infectivity assays (Table 4, below), which represent a recognized surrogate in vitro system to predict plasma drug concentrations required for viral inhibition in vivo. These comparisons revealed that T1249 is more potent against all HIV-1 isolates tested to date, with all Vn/Vo=0.1 (dose required to reduce virus titer by one log) values being reduced to sub-microgram concentrations. Many of the least sensitive clinical isolates to T20 exhibited 10-fold or greater sensitivity to T1249. It is noteworthy that HIV-1 9320, the isolate used in the HUPBMC SCID mouse model of infection, is 46-fold less sensitive to T20 than to T1249, indicating a very good correlation with the in vivo results.

TABLE 4 T20 T1249 Vn/Vo = 0.1 Vn/Vo = 0.1 Fold Virus Isolate (HIV-1 (ng/ml) (ng/ml) Difference IIIB 250 80 3 9320 6000 130 46 301714 (subtype B, 8000 700 11 NSI) 302056 (subtype B, 800 90 9 NSI) 301593 (subtype B, SI) 3500 200 18 302077 (subtype A) 3300 230 14 302143 (SI) 1600 220 7 G691-2 (AZT-R) 1300 400 3

7.2.4. ANTIVIRAL ACTIVITY—T20 RESISTANT LAB ISOLATES

T1249 was directly compared to T20 in virus mediated cell—cell fusion assays conducted using chronically infected CEM cells mixed with uninfected Molt-4 cells (Table 5, below). T1249 was nearly 200-fold more potent than T20 against a T20-resistant isolate.

TABLE 5 T20 T1249 Fold Virus Isolate (ng/ml) n (ng/ml) n Difference HIV-1 pNL4-3 SM 405.3 3 2.1 3 193 (T20 Resistant)

In Magi-CCR-5 assays (see Table 6, below), T1249 is as much as 50,000-fold more potent than T20 against T20-resistant isolates such as pNL4-3 SM and pNL4-3 STM (Rimskyl L. and Matthews, T., 1998, J. Virol. 72:986-993).

TABLE 6 T20 T1249 EC-50 Vn/Vo = 0.1 Virus Vn/Vo = Vn/Vo = Fold Fold Isolate EC-50 0.1 EC-50 0.1 Difference Difference HIV-1 pNL4-3 166 210 1 13 166 16 pNL4-3 SM 90 900 4 11 23 82 (T20-R) pNL4-3 SM 410 2600 4 11 103 236 (T20-R) Duke pNL4-3 >50000 >50000 1 13 >50000 >3846 STM (T20/T649- R) Duke

T1249 was directly compared to T20 in HuPBMC infectivity assays (see Table 7, below), evaluating differences in potency against a resistant isolate. T1249 is greater than 250-fold more potent than T20 against the resistant isolate pNL4-3 SM.

TABLE 7 T20 T1249 Vn/Vo = 0.1 Vn/Vo = 0.1 Fold Virus Isolate (HIV-1 (ng/ml) (ng/ml) Difference HIV-1 pNL4-3 3500 30 117 pNL4-3 SM (T20-R) >10000 40 >250

7.2.5. ANTIVIRAL ACTIVITY—IN VIVO SCID-HuPBMC MODEL

In vivo antiviral activity of T1249 was directly compared to T20 activity in the HuPBMC-SCID mouse model of HIV-1 9320 infection (FIG. 3). Two weeks after reconstitution with HuPBMCs, mice were infected IP on day 0 with 10³ TCID₅₀ HIV-19320 passed in PBMCs (AZT-sensitive isolate A018). Treatment with peptides was IP, bid, for total daily doses of 67 mg/kg (T20), 20 mg/kg (T1249), 6.7 mg/kg (T1249), 2.0 mg/kg (T1249), and 0.67 mg/kg (T1249), for 8 days beginning on day -1. The extent of infection in blood cells, splenocytes, lymph nodes, and peritoneal cells was assayed by quantitative co-culture with human PBMC blasts weekly for three consecutive weeks following animal exanguinations and tissue harvest (day 7, approx. 12 to 18 hours following last drug treatment). Co-culture supernatants were evaluated for HIV-1 p24 antigen production as a measure of virus infection. Infectious virus was not detectable in the blood or lymph tissues of the T20-treated animals, although, virus was detected in the peritoneal washes and spleen preparation. All compartments were negative for infectious virus at the 6.7 mg/kg dose of T1249, indicating at least a 10-fold improvement over T20 treatment. At the 2.0 mg/kg dose of T1249, both the lymph and the spleen were completely free of detectable infectious virus, with a 2 log₁₀ reduction in virus titer in the peritoneal wash and a 1 log₁₀ reduction in virus titer in the blood, compared to infected controls. At the lowest dose of T1249, 0.67 mg/kg, the peritoneal washes and blood were equivalent to infected control; however, at least a 1 log₁₀ drop in infectious virus titer was observed in both the lymph and the spleen tissues. Overall, the results indicate that T1249 is between 30 and 100-fold more potent against HIV-1 9320, in vivo, under these conditions.

7.2.6. PHARMACOKINETIC STUDIES—RAT

Cannulated rats were used to further define the pharmacokinetic profile of T1249. Male CD rats, 250-300 g, were dosed IV through a jugular catheter with T1249 and T20 (FIGS. 4A-5). The resulting plasma samples were evaluated using fluorescence HPLC to estimate peptide quantities in extracted plasma. The beta-phase half-life and total AUC of T1249 was nearly three times greater than T20 (FIG. 5).

7.2.7. CYTOTOXICITY

No overt evidence of T1249 cytotoxicity has been observed in vitro, as demonstrated in FIG. 6.

In addition, T1249 is not acutely toxic (death within 24 hours) at 167 mg/kg (highest dose tested) given IV through jugular cannula (0.3 ml over 2-3 min).

7.2.8. DIRECT BINDING TO gp41 CONSTRUCT M41Δ178

T1249 was radiolabeled with ¹²⁵I and HPLC- purified to maximum specific activity. T20 was iodinated in the same manner. Saturation binding of to M41Δ178 (a truncated gp41 actodomain fusion protein lacking the T20 amino acid sequence) immobilized on microtitre plates at 0.5 mg/μl is shown in FIGS. 7A-B. Nonspecific binding was defined as binding of the radioligand in the presence of 1 μM unlabeled peptide. Specific binding was the difference between total and nonspecific binding. The results demonstrate that ¹²⁵I-T1249 and ¹²⁵I-T20 have similar binding affinities of 1-2 nM. Linear inverse Scatchard plots suggests that each ligand binds to a homogeneous class of sites.

The kinetics of ¹²⁵I-T1249 and ¹²⁵I-T20 binding was determined on scintillating microtitre plates coated with 0.5 μg/ml M41Δ178. The time course for association and dissociation is shown in FIGS. 8A-B. Dissociation of bound radioligand was measured following the addition of unlabeled peptide to a final concentration of 10 μM in one-tenth of the total assay volume. Initial on- and off-rates for ¹²⁵I-T 1249 were significantly slower than those of ¹²⁵I-T20. Dissociation patterns for both radioligands were unchanged when dissociation was initiated with the other unlabeled peptide (i.e., ¹²⁵I-T1249 with T20).

To further demonstrate that both ligands compete for the same target site, unlabeled T1249 and T20 were titrated in the presence of a single concentration of either ¹²⁵I-T1249 or ¹²⁵I-T20. Ligand was added just after the unlabeled peptide to start the incubation. The competition curves shown in FIGS. 9A-B suggest that although both ligands have similar affinities, a higher concentration of unlabeled peptide is required to fully compete for bound ¹²⁵I-T 1249.

8. EXAMPLE: RESPIRATORY SYNCYTIAL VIRUS HYBRID POLYPEPTIDES

The following example describes respiratory syncytial virus (RSV) hybrid polypeptides with enhanced pharmacokinetic properties. In addition, results are presented, below, which demonstrate that the RSV hybrid polypeptides represent potent nhibitors of RSV infection.

8.1. MATERIALS AND METHODS 8.1.1. PEPTIDE-SYNTHESIS AND PURIFICATION

RSV polypeptides were synthesized using standard Fast Moc chemistry. Generally, unless otherwise noted, the peptides contained amidated carboxyl termini and acetylated amino termini. Purification was carried out by reverse phase HPLC.

8.1.2. RESPIRATORY SYNCYTIAL VIRUS PLAQUE REDUCTION ASSAY

All necessary dilutions of peptides were performed in clean, sterile 96-well TC plate. A total of eleven dilutions for each peptide and one control well containing no peptide were assembled. The final concentration range of peptide started at 50 μg/ml or 100 μg/ml, with a total of eleven two-fold dilutions. The RSV was prepared at a concentration of 100PFU/well in 100 μl 3%EMEM, as determined by a known titer of RSV. The virus is then added to all of the wells.

The media was removed from one sub-confluent 96-well plate of Hep2 cells. The material from the dilution plate was transferred onto the cell plates starting with row 1 and then transferring row 12, row 11, etc. until all rows were transferred. Plates were placed back into the incubator for 48 hours.

The cells were checked to ensure that syncytia were present in the control wells. Media was removed and approximately 50 μls of 0.25% Crystal Violet in methanol was added to each well. The wells were rinsed immediately in water to remove excess stain and allowed to dry. Using a dissecting microscope, the number of syncytia in each well was counted.

8.2. RESULTS

Pharmacokinetic studies with the RSV hybrid peptides T1301 (Ac-WQEWDEYDASISQVNEKINQALAYIREADELWAWF-NH2) (SEQ ID NO: 1122) and T1302 (Ac-WQAWDEYDASISQVNEKINQALAYIREADELWAWF-NH2) (SEQ ID NO: 1123) containing enhancer peptide sequences demonstrated a greatly enhanced half-life relative to core peptide T786 (Ac-VYPSDEYDASISQVNEEINQALAYIRKADELLENV-NH2) (SEQ ID NO:692), as demonstrated in FIGS. 10A-10B. Hybrid polypeptides T1301, T1302 and T1303 (Ac-WQAWDEYDASISDVNEKINQALAYIREADELWEWF-NH2) (SEQ ID NO:1124) also showed a greatly enhanced half-size relative to core peptide T1476 (Ac-DEYDASISQVNEKINQALAYIREADEL-NH2) (SEQ ID NO: 1416).

RSV hybrid polypeptides T1301, T1302 and T1303, as well as polypeptide T786 and T1293, were tested for their ability to inhibit RSV plaque formation of HEp2 cells. As indicated in FIGS. 11A and 11B, both the tested hybrid RSV polypeptides, as well as the T786 core polypeptide were able to inhibit RSV infection. Surprisingly, the T1293 hybrid polypeptide was also revealed to be a potent anti-RSV compound (FIGS. 13A-D).

9. EXAMPLE: LUTEINIZING HORMONE HYBRID POLYPEPTIDES

The example presented herein describes luteinizing hormone (LH) hybrid proteins with enhanced pharmacokinetic properties. The following LH hybrid peptides were synthesized and purified using the methods described above: core peptide T1323 (Ac-QHWSYGLRPG-NH2) (SEQ ID NO: 1143) and hybrid polypeptide T1324 (Ac-WQEWEQKIQHWSYGLRPGWASLWEWF-NH2) (SEQ ID NO: 1144) which comprises the core polypeptide T1323 amino acid sequence coupled with enhancer peptides at its amino- and carboxy-termini. As demonstrated in FIGS. 12A and 12B, the T1324 hybrid peptide exhibited a significantly increased half-life when compared to the T1323 core peptide which lacks the enhancer peptide sequences.

The present invention is not to be limited in scope by the specific embodiments described herein, which are intended as single illustrations of individual aspects of the invention, and functionally equivalent methods and components are within the scope of the invention. Indeed, various modifications of the invention, in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

SEQUENCE LISTING The patent contains a lengthy “Sequence Listing” section. A copy of the “Sequence Listing” is available in electronic form from the USPTO web site (http://seqdata.uspto.gov/sequence.html?DocID=06562787B1). An electronic copy of the “Sequence Listing” will also be available from the USPTO upon request and payment of the fee set forth in 37 CFR 1.19(b)(3). 

What is claimed is:
 1. A pharmaceutical composition comprising an effective amount of (a) a hybrid polypeptide comprising an enhancer peptide linked to a core polypeptide, wherein the enhancer peptide comprises an amino-terminal: WXXWXXXI, WXXWXXX, WXXWXX, WXXWX, WXXW, WXXXWXWX, XXXWXWX, XXWXWX, XWXWX, WXWX, WXXXWXW, WXXXWX, WXXXW, IXXXWXXW, XXXWXXW, XXWXXW, XWXXW, XWXWXXXW, XWXWXXX, XWXWXX, XWXW, WXWXXXW, or XWXXXW, and wherein the core polypeptide comprises TALLEQAQIQQEKNEYELQKLDK (SEQ.ID NO:1286); and (b) another therapeutic agent.
 2. The pharmaceutical composition of claim 1, wherein the hybrid polypeptide further comprises a carboxy-terminal enhancer peptide.
 3. A pharmaceutical composition comprising an effective amount of a) a hybrid polypeptide comprising an enhancer peptide linked to a core polypeptide, wherein the enhancer peptide comprises a carboxy-terminal: WXXWXXXI, WXXWXXX, WXXWXX, WXXWX, WXXW, WXXXWXWX, XXXWXWX, XXWXWX, XWXWX, WXWX, WXXXWXW, WXXXWX, WXXXW, IXXXWXXW, XXXWXXW, XXWXXW, XWXXW, XWXWXXXW, XWXWXXX, XWXWXX, XWXW, WXWXXXW, or XWXXXW, and wherein the core polypeptide comprises TALLEQAQIQQEKNEYELQKLDK (SEQ ID NO:1286); and (b) another therapeutic agent.
 4. The pharmaceutical composition of claim 1, wherein the hybrid polypeptide further comprises an amino-terminal enhancer peptide.
 5. A pharmaceutical composition comprising an effective amount of (a) a hybrid polypeptide comprising an enhancer peptide sequence linked to a core polypeptide, wherein the enhancer peptide sequence comprises WQEWEQKI (SEQ ID NO: 1129) or WASLWEWF (SEQ ID NO: 1433) and the core polypeptide comprises TALLEQAQIQQEKNEYELQKLDK (SEQ ID NO: 1286); and (b) another therapeutic agent.
 6. A pharmaceutical composition comprising an effective amount of a polypeptide comprising WQEWEQKITALLEQAQIQQEKNEYELQKLDKWASLWEWF (SEQ ID NO: 1310); and another therapeutic agent.
 7. A pharmaceutical composition comprising an effective amount of a polypeptide comprising TALLEQAQIQQEKNEYELQKLDK (SEQ ID NO: 1286); and another therapeutic agent.
 8. The pharmaceutical composition of any of claims 1-7, wherein the polypeptide further comprises an amino terminal acetyl group and a carboxy terminal amido group.
 9. The pharmaceutical composition of any of claims 1-7, further comprising a pharmaceutically acceptable carrier.
 10. The pharmaceutical composition of any of claims 1-7, wherein the other therapeutic agent is an antiviral agent.
 11. The pharmaceutical composition of claim 10, wherein the antiviral agent is DP-107, DP-178, a cytokine, a reverse transcriptase inhibitor, a viral mRNA capping inhibitor, a viral protease inhibitor, a lipid-binding molecule with anti-HIV activity, or an inhibitor of glycoprotein processing.
 12. A method for inhibiting HIV infection comprising administering to a patient in need thereof an effective amount of a hybrid polypeptide comprising an enhancer peptide linked to a core polypeptide, wherein the enhancer peptide comprises an amino-terminal: WXXWXXXI, WXXWXXX, WXXWXX, WXXWX, WXXW, WXXXWXWX, XXXWXWX, XXWXWX, XWXWX, WXWX, WXXXWXW, WXXXWX, WXXXW, IXXXWXXW, XXXWXXW, XXWXXW, XWXXW, XWXWXXXW, XWXWXXX, XWXWXX, XWXW, WXWXXXW, or XWXXXW, and wherein the core polypeptide comprises TALLEQAQIQQEKNEYELQKLDK(SEQ ID NO: 1286).
 13. The method of claim 12, wherein the hybrid polypeptide further comprises a carboxy-terminal enhancer peptide.
 14. A method for inhibiting HIV infection comprising administering to a patient in need thereof an effective amount of a hybrid polypeptide comprising an enhancer peptide linked to a core polypeptide, wherein the enhancer peptide comprises a carboxy-terminal: WXXWXXXI, WXXWXXX, WXXWXX, WXXWX, WXXW, WXXXWXWX, XXXWXWX, XXWXWX, XWXWX, WXWX, WXXXWXW, WXXXWX, WXXXW, IXXXWXXW, XXXWXXW, XXWXXW, XWXXW, XWXWXXXW, XWXWXXX, XWXWXX, XWXW, WXWXXXW, or XWXXXW, and wherein the core polypeptide comprises TALLEQAQIQQEKNEYELQKLDK (SEQ ID NO:1286).
 15. The method of claim 14, wherein the hybrid polypeptide further comprises an amino-terminal enhancer peptide.
 16. A method for inhibiting HIV infection comprising administering to a patient in need thereof an effective amount of a hybrid polypeptide comprising an enhancer peptide sequence linked to a core polypeptide, wherein the enhancer peptide sequence comprises WQEWEQKI (SEQ ID NO:1129) or WASLWEWF (SEQ ID NO:1433) and the core polypeptide comprises TALLEQAQIQQEKNEYELQKLDK (SEQ ID NO: 1286).
 17. A method for inhibiting HIV infection comprising administering to a patient in need thereof an effective amount of a polypeptide comprising WQEWEQKITALLEQAQIQQEKNEYELQKLDKWASLWEWF (SEQ ID NO: 1310).
 18. A method for inhibiting HIV infection comprising administering to a patient in need thereof an effective amount of a polypeptide comprising TALLEQAQIQQEKNEYELQKLDK (SEQ ID NO:1286).
 19. The method of any of claims 12-18, wherein the polypeptide further comprises an amino terminal acetyl group and a carboxy terminal amido group.
 20. The method of claim 19 further comprising administering a pharmaceutically acceptable carrier.
 21. The method of any of claims 12-18 further comprising administering a pharmaceutically acceptable carrier.
 22. The method of claim 21, wherein the administering is performed via oral, rectal, vaginal, lung, transdermal, transmucosal, intestinal, parenteral, intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intravenous, intraperitoneal, intranasal or intraocular route.
 23. The method of claim 21 further comprising administering an effective amount of at least one other therapeutic agent.
 24. The method of claim 23, wherein the other therapeutic agent is an antiviral agent.
 25. The method of claim 24, wherein the antiviral agent is DP-107, DP-178, a cytokine, a reverse transcriptase inhibitor, a viral mRNA capping inhibitor, a viral protease inhibitor, a lipid-binding molecule with anti-HIV activity, or an inhibitor of glycoprotein processing.
 26. The method of claim 25, wherein the administering is performed concomitantly, sequentially, with interruption or by cycling therapy.
 27. The method of claim 20 or claim 23, wherein the administering is performed via oral, rectal, vaginal, lung, transdermal, transmucosal, intestinal, parenteral, intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intravenous, intraperitoneal, intranasal or intraocular route.
 28. The composition of claim 11 wherein the antiviral agent is DP-107.
 29. The composition of claim 11 wherein the antiviral agent is DP-
 178. 30. The composition of claim 11 wherein the antiviral agent is a cytokine.
 31. The composition of claim 11 wherein the antiviral agent is a reverse transcriptase inhibitor.
 32. The composition of claim 11 wherein the antiviral agent is a viral mRNA capping inhibitor.
 33. The composition of claim 11 wherein the antiviral agent is a viral protease inhibitor.
 34. The composition of claim 11 wherein the antiviral agent is a lipid-binding molecule with anti-HIV activity.
 35. The composition of claim 11 wherein the antiviral agent is an inhibitor of glycoprotein processing.
 36. The method of claim 22 wherein the administering is performed via subcutaneous route.
 37. The method of claim 22 wherein the administering is performed via intravenous route.
 38. The method of claim 25 wherein the antiviral agent is DP-107.
 39. The method of claim 25 wherein the antiviral agent is DP-178.
 40. The method of claim 25 wherein the antiviral agent is a cytokine.
 41. The method of claim 25 wherein the antiviral agent is a reverse transcriptase inhibitor.
 42. The method of claim 25 wherein the antiviral agent is a viral mRNA capping inhibitor.
 43. The method of claim 25 wherein the antiviral agent is a lipid-binding molecule with anti-HIV activity.
 44. The method of claim 25 wherein the antiviral agent is an inhibitor of glycoprotein processing.
 45. The method of claim 27 wherein the administering is performed via subcutaneous route.
 46. The method of claim 27 wherein the administering is performed via intravenous route.
 47. The method of claim 12 wherein the enhancer peptide comprises an amino-terminal: WXXWXXXI.
 48. The method of claim 12 wherein the enhancer peptide comprises an amino-terminal: WXXXWXWX.
 49. The method of claim 12 wherein the enhancer peptide comprises an amino-terminal: IXXXWXXW.
 50. The method of claim 12 wherein the enhancer peptide comprises an amino-terminal: XWXWXXXW.
 51. The method of claim 14 wherein the enhancer peptide comprises a carboxy-terminal: WXXWXXXI.
 52. The method of claim 14 wherein the enhancer peptide comprises a carboxy-terminal: WXXXWXWX.
 53. The method of claim 14 wherein the enhancer peptide comprises a carboxy-terminal: IXXXWXXW.
 54. The method of claim 14 wherein the enhancer peptide comprises a carboxy-terminal: XWXWXXXW. 